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WO2025119569A1 - Protease variants with improved bleach stability - Google Patents

Protease variants with improved bleach stability Download PDF

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Publication number
WO2025119569A1
WO2025119569A1 PCT/EP2024/081351 EP2024081351W WO2025119569A1 WO 2025119569 A1 WO2025119569 A1 WO 2025119569A1 EP 2024081351 W EP2024081351 W EP 2024081351W WO 2025119569 A1 WO2025119569 A1 WO 2025119569A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
protease
positions
group
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/081351
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German (de)
French (fr)
Inventor
Christian DEGERING
Shohana ISLAM
Margret VAN LIER
Antje Gebert-Schwarzwaelder
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Henkel AG and Co KGaA
Original Assignee
Henkel AG and Co KGaA
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Filing date
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Publication of WO2025119569A1 publication Critical patent/WO2025119569A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
    • C12N9/54—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea bacteria being Bacillus
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/38—Products with no well-defined composition, e.g. natural products
    • C11D3/386—Preparations containing enzymes, e.g. protease or amylase
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/39—Organic or inorganic per-compounds
    • C11D3/3902—Organic or inorganic per-compounds combined with specific additives
    • C11D3/3905—Bleach activators or bleach catalysts
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21062—Subtilisin (3.4.21.62)

Definitions

  • the invention lies in the field of enzyme technology.
  • the invention relates to proteases whose amino acid sequence has been modified, particularly with regard to use in detergents and cleaning agents, in particular with regard to automatic dishwashing detergents, in order to improve their stability, in particular their stability in the presence of bleach, and to the nucleic acids encoding them and their preparation.
  • the invention further relates to the uses of these proteases and methods in which they are used, as well as to detergents and cleaning agents containing them, in particular detergents and cleaning agents containing bleach, preferably automatic dishwashing detergents, particularly preferably automatic dishwashing detergents containing bleach.
  • proteases are among the most technically important enzymes of all. They are the longest-established enzymes in detergents and cleaning agents and are contained in virtually all modern, high-performance detergents and cleaning agents. They break down protein-containing soils on the items being cleaned. Among these, proteases of the subtilisin type (subtilases, subtilopeptidases, EC 3.4.21.62) are particularly important. These are serine proteases due to the catalytically active amino acids. They act as nonspecific endopeptidases and hydrolyze any acid amide bonds found within peptides or proteins. Their pH optimum is usually in the significantly alkaline range. An overview of this family is provided, for example, in the article "Subtilases: Subtilisin-like Proteases" by R.
  • subtilisin Enzymes edited by R. Bott and C. Betzel, New York, 1996.
  • Subtilases are naturally produced by microorganisms. Among them, the subtilisins, produced and secreted by Bacillus species, are particularly noteworthy as the most important group within the subtilases.
  • subtilisin-type proteases preferably used in detergents and cleaning agents are the subtilisins BPN' and Carlsberg, the protease PB92, the subtilisins 147 and 309, the alkaline protease from Bacillus lentus, in particular from Bacillus lentus DSM 5483, subtilisin DY, and the enzymes thermitase, proteinase K, and the proteases TW3 and TW7, which are classified as subtilases but no longer as subtilisins in the narrower sense, as well as variants of the aforementioned proteases that have an amino acid sequence that is altered compared to the parent protease.
  • Proteases are modified in a targeted or random manner using methods known from the state of the art and thus optimized, for example, for use in detergents and cleaning agents. These include point, deletion, or insertion mutagenesis, or fusion with other proteins or protein fragments. For most of the proteases known from the state of the art, optimized variants are known.
  • WO 2017/215925 discloses a protease from Bacillus gibsonii or variants thereof intended for use in detergents and cleaning agents.
  • proteases are suitable for use in preparations containing surfactants and/or bleaching agents. Many proteases do not show any sufficient catalytic performance or they are not sufficiently stable. For the use of proteases in washing and cleaning agents, high catalytic activity and stability under conditions such as those encountered during a washing or cleaning process are therefore particularly desirable. Consequently, prior art formulations containing proteases, surfactants, and/or bleaching agents have the disadvantage that the proteases they contain do not have satisfactory proteolytic activity and/or are not sufficiently stable under standard washing and/or cleaning conditions, and the formulations therefore do not demonstrate optimal cleaning performance on protease-sensitive soils.
  • Protease-sensitive soils are preferably selected from the group consisting of blood, egg (yolk), milk, and other protein-containing soils.
  • Protein-containing soils especially egg soils, and bleachable soils, especially tea soils, are stubborn stains that are often not satisfactorily removed.
  • Such soils, especially bleachable soils are typically addressed by adding bleaching agents to detergents and cleaning products.
  • bleaching agents are unstable in the presence of bleaching and/or oxidizing agents and lose their activity. This is especially true for liquid detergents and cleaning products. Therefore, the washing and cleaning performance of conventional detergents and cleaning products that combine enzymes and bleaching agents in one composition is greatly reduced.
  • a protease from Bacillus gibsonii or a sufficiently similar protease which, based on the numbering according to SEQ ID NO:1, has (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution, which is selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, is improved with regard to its stability
  • the invention therefore relates to a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid
  • a preferred subject of the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino
  • a further preferred subject of the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one, preferably two of the positions corresponding to positions 211 and 212, at least one, preferably two amino acid substitution(s) selected from the group consisting
  • the invention further relates to a process for the preparation of a protease, comprising introducing (i) at least one amino acid substitution at at least one of the positions which, based on the numbering according to SEQ ID NO:1, correspond to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one amino acid substitution at at least one of the positions which, based on the numbering according to SEQ ID NO:1, correspond to positions 29, 58, 89, 117 and 216, selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, into a starting molecule having an amino acid sequence which
  • a protease within the meaning of the present patent application therefore encompasses both the protease itself and a protease produced by a process according to the invention. All statements regarding the protease therefore refer both to the protease itself and to the proteases produced by corresponding processes, as well as to the corresponding processes, in particular to the production processes of the protease.
  • proteases according to the invention relate to the nucleic acids encoding these proteases, proteases according to the invention or nucleic acids containing non-human host cells and washing and cleaning agents comprising proteases according to the invention, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, washing and cleaning methods, and uses of the proteases according to the invention in washing or cleaning agents, in particular Bleach-containing washing and cleaning agents, preferably automatic dishwashing detergents, particularly preferably bleach-containing automatic dishwashing detergents, for removing protease-sensitive soiling.
  • Numerical ranges specified in the format "from x to y" include the specified values. If multiple preferred numerical ranges are specified in this format, it goes without saying that all ranges resulting from the combination of the different endpoints will also be included.
  • At least one as used herein means one or more, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more.
  • washing and cleaning agent or “washing or cleaning agent” as used herein is synonymous with the term “agent” or “composition” or “washing and/or cleaning agent composition” and refers to a composition for cleaning textiles and/or hard surfaces, in particular dishes, as explained in the description.
  • composition or agent contains less than 2% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight and most preferably less than 0.1% by weight of the corresponding substance, based on the total weight of the composition/agent.
  • Liquid includes liquids and gels, as well as pasty compositions. It is preferred that the liquid compositions be flowable and pourable at room temperature, but it is also possible that they have a yield point.
  • a substance e.g. a composition or an agent, is solid according to the definition of the invention if it is in the solid state at 25°C and 1,013 mbar.
  • a substance e.g., a composition or agent
  • Liquid also includes gel.
  • Variant refers to natural or artificially produced variations of a native protease that have a modified amino acid sequence compared to the reference form.
  • the present invention is based on the surprising discovery of the inventors that amino acid substitutions at the positions described herein result in improved stability of this modified protease in detergents and cleaning agents, in particular detergents and cleaning agents containing bleach, preferably automatic dishwashing detergents, particularly preferably automatic dishwashing detergents containing bleach.
  • the present invention is based in particular on the surprising discovery of the inventors that amino acid substitutions at the positions described herein result in improved stability of this modified protease in the presence of bleaching agents, in particular oxidizing agents.
  • the changes according to the invention (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, leads to improved stability of this modified protease in washing and cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach.
  • the changes according to the invention (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, leads to improved stability of this modified protease in the presence of bleaching agents, in particular oxidizing agents.
  • the protease (i) according to the invention has at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the combination of the at least one amino acid substitution from group (i) and the at least one amino acid substitution from group (ii) leads to improved stability of this modified protease in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach.
  • the protease according to the invention has (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the combination of the at least one amino acid substitution from group (i) and the at least one amino acid substitution from group (ii) leads to improved stability of this modified protease in the presence of bleaching agents, in particular oxid
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to that shown in SEQ ID NO:1 specified amino acid sequence over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1 , (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, where the protease, each with reference to the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L, P212D
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, has (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO: 1, has (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M211 L-P212D-A29G, M211 L-P212D-A29G-D58P,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D
  • the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M1171, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A
  • the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L- P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A
  • the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V-M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D-M216F, D58P-M211 L-P212D-M216A and M211 L-P212D-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO:1 and wherein the Protease does not contain any further changes besides the amino acid substitutions mentioned.
  • the combinations of the amino acid substitutions according to the invention from groups (i) and (ii) described herein lead to improved cleaning performance of this modified protease in washing or cleaning agents, in particular bleach-containing washing and cleaning agents, preferably automatic dishwashing agents, particularly preferably bleach-containing automatic dishwashing agents, on at least one protease-sensitive soil.
  • Proteases according to the invention therefore enable improved removal of at least one, preferably several, protease-sensitive soils on textiles and/or hard surfaces, in particular dishes.
  • Typical protease-sensitive soils include, for example, egg (yolk), blood, milk, and other protein-containing soils.
  • An improvement in cleaning performance according to the invention is present when the protease shows improved cleaning performance compared to a reference protease on at least one protease-sensitive soil, which is preferably selected from the group consisting of blood, egg (yolk), milk and other protein-containing soils.
  • the combinations of the amino acid substitutions from groups (i) and (ii) described herein lead to improved stability of this modified protease in washing or cleaning agents, in particular bleach-containing washing or cleaning agents, preferably automatic dishwashing agents, particularly preferably bleach-containing automatic dishwashing agents.
  • the combinations of the amino acid substitutions from groups (i) and (ii) described herein lead to improved stability of this modified protease in the presence of bleaching agents, in particular oxidizing agents.
  • Proteases according to the invention can therefore be used in washing or cleaning agents, in particular bleach-containing washing and cleaning agents, preferably automatic dishwashing agents, particularly preferably bleach-containing automatic dishwashing agents.
  • Proteases according to the invention can therefore be used in washing or cleaning agents, in particular bleach-containing washing and cleaning agents, preferably automatic dishwashing agents, particularly preferably bleach-containing automatic dishwashing agents, and exhibit a cleaning performance in such agents.
  • proteases according to the invention can improve the cleaning performance of bleach- and enzyme-containing, in particular protease-containing, washing and cleaning agents, in particular automatic dishwashing agents, particularly with regard to protease-sensitive soils.
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case with reference to the numbering according to SEQ ID NO:1, (i) an amino acid substitution or Amino acid substitution combination selected from the group consisting of 143V, M122L-N154S-T156A, M211 N-P212
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% is identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or
  • Amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H and Q12L-M122L-A222S, and (ii) an amino acid substitution or amino acid substitution combination selected from the group consisting of M117A, M117A-Y89L, M117V, M117V-A29G, M117F, M117I, M117L, M216F, D58P-M216A, M216L, wherein the protease has improved stability in washing or cleaning agents, in particular bleach-containing washing and cleaning agents, preferably Dishwashing detergents, particularly preferably dishwashing detergents containing bleach, the stability being determined as described in Example 3.
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M211 L-P212D-A29G, M211 L-P212D-A29G-D58P,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D
  • the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M1171, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-N-N
  • N154S-T156A-D58P-Y89A-M117I M122L-N154S-T156A-D58P-Y89A-M117L, M122L-N154S-T156A- D58P-Y89A-M117V, M122L-N154S-T156A-D58P-Y89A-M216A, M122L-N154S-T156A-D58P-Y89A-M216F, M122L-N154S-T156A-D58P-Y89A-M216L, M122L-N154S-T156A-D58P-M117A-M216A, M122L-N154S-T156A-D58P-M117A-M216F, M122L-N154S-T156A-D58P-M117A-M216L, M122L-N154S-T156A-D58P-M117A-M216L, M122L-N154S-T156A-D58P-M117A
  • the protease according to the invention comprises a M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M117I, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G- M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G- D58P-M117F, M211 L-P212
  • the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V-M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D-M216F, D58P-M211 L-P212D-M216A and M211 L-P212D-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO:1, wherein the Protease comprises no further changes besides the amino acid substitutions mentioned, and wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, the stability being determined as described
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, has two amino acid substitutions selected from the group consisting of M211N, M211L
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO: 1, has an amino acid substitution combination which is selected from the group consisting of M211 L-P212D-A29G, M211 L-P212D-A29G-D58P,
  • the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D
  • the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M1171, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-N-N
  • the protease according to the invention comprises a M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M117I, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G- M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G- D58P-M117F, M211 L-P212
  • the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V-M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D-M216F, D58P-M211 L-P212D-M216A and M211 L-P212D-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO:1, wherein the Protease comprises no further changes besides the amino acid substitutions mentioned, and wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.
  • proteases according to the invention have increased catalytic activity in washing and cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach.
  • the proteases according to the invention can have a proteolytic activity of at least 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, or more, based on the wild type (SEQ ID NO:1).
  • Such performance-enhanced proteases enable improved cleaning results on protease-sensitive soils.
  • Such performance-improved cleaning results on protease-sensitive soils can be achieved in various temperature ranges, e.g. in a range from about 0°C to about 100°C, preferably about 20°C to about 75°C, more preferably about 30°C to about 60°C, particularly preferably about 40°C to about 55°C.
  • proteases according to the invention have high stability in detergents and cleaning agents, in particular detergents and cleaning agents containing bleach, preferably automatic dishwashing detergents, particularly preferably automatic dishwashing detergents containing bleach.
  • proteases according to the invention also have high stability, e.g., towards surfactants and/or chelators, and/or towards temperature influences, in particular towards high temperatures, e.g., between about 50°C and about 65°C, in particular about 60°C, and/or towards acidic or alkaline conditions and/or towards pH changes and/or towards denaturing or oxidizing agents and/or towards (auto)proteolytic degradation and/or towards a change in redox ratios.
  • proteases according to the invention have enzymatic activity, ie they are capable of hydrolyzing peptides and proteins, particularly in washing and cleaning agents.
  • the protease according to the invention is therefore an enzyme which catalyzes the hydrolysis of amide/peptide bonds in protein/peptide substrates and is thus able to cleave proteins or peptides.
  • a protease according to the invention is preferably a mature protease, i.e., the catalytically active molecule without signal and/or propeptide(s). Unless otherwise stated, the sequences indicated also refer to mature (processed) enzymes.
  • the protease is a free enzyme. This means that the protease can interact directly with all components of a composition and, if the composition is a liquid composition, that the protease is in direct contact with the composition's solvent (e.g., water).
  • a composition may contain proteases that form an interaction complex with other molecules or that contain a "coat.”
  • a single or multiple protease molecules may be separated from the other components of the composition by a surrounding structure.
  • a separating structure may be formed by, but is not limited to, vesicles, such as a micelle or a liposome.
  • the surrounding structure may also be a virus particle, a bacterial cell, or a eukaryotic cell.
  • an agent may contain cells of, for example, Bacillus pumilus or Bacillus subtilis or other expression strains expressing the proteases of the invention, or cell culture supernatants of such cells.
  • sequence comparison is based on the BLAST algorithm, which is established and commonly used in the state of the art (see, for example, Altschul et al., Basic local alignment search tool, J. Mol. Biol., 1990, 215:403-410, and Altschul et al., Gapped BLAST and PSI-BLAST: a new generation of protein database search programs, Nucleic Acids Res., 1997, 25:3389-3402) and is essentially performed by matching similar sequences of nucleotides or amino acids in the nucleic acid or amino acid sequences. A tabular assignment of the relevant positions is referred to as an alignment.
  • Sequence comparisons are created using computer programs. Frequently used programs are, for example, the Clustal series (see, for example, Chenna et al., Multiple sequence alignment with the Clustal series of programs, Nucleic Acid Res., 2003, 31:3497-3500), T-Coffee (see, for example, Notredame et al., T-Coffee: A novel method for multiple sequence alignments, J. Mol. Biol., 2000, 302:205-217) or programs based on these programs or algorithms.
  • Sequence comparisons are also possible using the computer program Vector NTI® Suite 10.3 (Invitrogen Corporation, 1600 Faraday Avenue, Carlsbad, California, USA) with the specified default parameters. Its AlignX module for sequence comparisons is based on ClustalW. Clone Manager 10 (using the BLOSUM 62 scoring matrix for sequence alignment at the amino acid level) or Clone Manager 10 (using the BLOSUM 62 scoring matrix for sequence alignment at the amino acid level) are also possible. Unless otherwise stated, the sequence identity stated herein is determined using the BLAST algorithm.
  • Such a comparison also allows a statement about the similarity of the compared sequences. This is usually expressed as percent identity, i.e. the proportion of identical Nucleotides or amino acid residues at the same or corresponding positions in an alignment are specified.
  • the broader term homology in amino acid sequences includes conserved amino acid substitutions, i.e. amino acids with similar chemical activity, since these usually exert similar chemical activities within the protein. Therefore, the similarity of the compared sequences can also be specified as percent homology or percent similarity.
  • Identity and/or homology statements can be made for entire polypeptides or genes or just for individual regions. Homologous or identical regions of different nucleic acid or amino acid sequences are therefore defined by similarities in the sequences. Such regions often have identical functions.
  • nucleic acid or amino acid sequence can be small and consist of only a few nucleotides or amino acids. Such small regions often exert essential functions for the overall activity of the protein. It can therefore be useful to relate sequence similarities only to individual, possibly small regions. Unless otherwise stated, details of identity or homology in the present application refer to the total length of the respective nucleic acid or amino acid sequence indicated.
  • an amino acid position corresponds to a numerically designated position in SEQ ID NO:1 therefore means that the corresponding position is assigned to the numerically designated position in SEQ ID NO:1 in an alignment as defined above.
  • the assignment of the positions is based on the mature protein. This assignment is also to be applied in particular if the amino acid sequence of a protease according to the invention comprises a higher number of amino acid residues than the protease according to SEQ ID NO:1.
  • the change positions in a protease according to the invention are those that are assigned to precisely these positions in an alignment.
  • proteases according to the invention can have further amino acid modifications, in particular amino acid substitutions, insertions or deletions.
  • Such proteases are further developed, for example, by targeted genetic modification, i.e., by mutagenesis methods, and optimized for specific applications or with regard to special properties (e.g., with regard to their catalytic activity, stability, etc.).
  • nucleic acids according to the invention can be introduced into recombination approaches and thus used to generate completely new types of proteases or other polypeptides. The aim is to introduce targeted mutations such as substitutions, insertions or deletions into the known molecules in order, for example, to improve the cleaning performance of enzymes according to the invention.
  • the surface charges and/or the isoelectric point of the molecules and thus their interactions with the substrate can be modified.
  • the net charge of the enzymes can be modified in order to influence substrate binding, particularly for use in detergents and cleaning agents.
  • one or more corresponding mutations can increase the stability or catalytic activity of the protease and thereby improve its purification performance.
  • Advantageous properties of individual mutations e.g., individual substitutions, can complement each other.
  • a protease that has already been optimized with regard to certain properties, e.g., with regard to its stability during storage and/or activity and/or their tolerance with respect to the substrate spectrum, can therefore be further developed within the scope of the invention.
  • amino acid exchanges amino acid exchanges
  • 130D/V thus means that position 130 is mutated to D or V.
  • additional amino acids are named after the sequence position.
  • deletions the missing amino acid is replaced by a symbol, e.g., an asterisk or a dash, or an A is indicated before the corresponding position.
  • P9T describes the substitution of proline at position 9 with threonine
  • P9TH the insertion of histidine after the amino acid threonine at position 9
  • P9* or AP9 the deletion of proline at position 9.
  • the invention therefore further provides a protease which is characterized in that it is obtainable from a protease as described herein as the starting molecule by single or multiple conservative amino acid substitution, wherein the protease has at least one of the amino acid substitutions described above in the numbering according to SEQ ID NO: 1.
  • conservative amino acid substitution means the exchange (substitution) of one amino acid residue for another amino acid residue, wherein this exchange does not lead to a change in the polarity or charge at the position of the exchanged amino acid, e.g., the exchange of one non-polar amino acid residue for another non-polar amino acid residue.
  • the protease is characterized in that it is obtainable from a protease according to the invention as starting molecule by fragmentation, deletion, insertion or substitution mutagenesis and comprises an amino acid sequence which corresponds to the starting molecule over a length of at least 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268 or 269 contiguous amino acids, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222
  • the enzymes retain their proteolytic activity even after mutagenesis, i.e., their proteolytic activity corresponds at least to that of the starting enzyme, i.e., in a preferred embodiment, the proteolytic activity is at least 100%, preferably at least 105%, more preferably at least 110%, even more preferably at least 120% or more, of the activity of the starting enzyme.
  • Other substitutions can also have advantageous effects. Both individual amino acids and multiple contiguous amino acids can be exchanged for other amino acids.
  • Advantageous positions for sequence changes, in particular substitutions, of the protease according to SEQ ID NO:1, which, when transferred to homologous positions of the proteases according to the invention, are preferably of importance and impart advantageous functional properties to the protease, are therefore the positions which, in an alignment, correspond to the positions described herein, i.e., in the numbering according to SEQ ID NO:1.
  • the following amino acid residues are located at the stated positions in the wild-type molecule of the protease: 29A, 58D, 89Y, 117M, 216M.
  • an amino acid exchange in a specific position of the protease according to SEQ ID NO:1 is accompanied by a change in an enzymatic parameter, e.g., an increase in the KM value, and a corresponding change in the enzymatic parameter, e.g., also an increase in the KM value, is observed in a protease variant according to the invention whose amino acid exchange was achieved by the same introduced amino acid, this is to be seen as confirmation of the correct assignment.
  • a process according to the invention for producing a protease comprises introducing (i) at least one amino acid substitution at at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, based on the numbering according to SEQ ID NO:1, selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one amino acid substitution at at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, based on the numbering according to SEQ ID NO:1, selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, into a starting molecule having an amino acid sequence which is at least 70% and increasingly preferably at
  • a method according to the invention may further comprise one or more of the following method steps:
  • the protease comprises an amino acid sequence which corresponds to the starting molecule over a length of at least 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268 or 269 contiguous amino acids, wherein the protease, in each case based on the numbering according to SEQ ID NO: 1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29,
  • a previously described protease is stabilized, in particular by one or more mutations, e.g., substitutions, or by coupling to a polymer.
  • mutations e.g., substitutions
  • all stabilization options described and/or expedient in the prior art are contemplated. Preference is given to stabilizations achieved via mutations of the enzyme itself, since such stabilizations do not require any further steps following the isolation of the enzyme. Examples of suitable sequence modifications are mentioned above. Other suitable sequence modifications are known from the prior art.
  • Preferred embodiments are those in which the enzyme is stabilized in several ways, since several stabilizing mutations act additively or synergistically.
  • the protease according to the invention can be reacted with at least one reversible inhibitor compound selected from the group consisting of peptide inhibitors, in particular peptide aldehydes, polyols, in particular glycerol and 1,2-propylene glycol, benzamidine hydrochloride, borax, boric acids, boronic acids or their salts or esters or derivatives, in particular phenylboronic acid derivatives or 4-formylphenylboronic acid (4-FPBA), compounds of the formulas (I) or (II) wherein R is in each case selected from -COOH, C 1-6 alkyl-substituted or unsubstituted C 2-6 dicarboxylic acids, C 1-6 alkyl-substituted or unsubstituted C 2-6 carboxylic acids and -OOC-NR 2 2, wherein R 2 is the same or different and is selected from C 1-5 alkyl or H, and salts, esters or derivatives thereof
  • the protease is characterized in that its cleaning performance is not significantly reduced compared to the wild-type enzyme (SEQ ID NO:1) (reference protease), i.e. it has at least 80% of the reference washing or cleaning performance, preferably at least 100%, more preferably at least 110%, particularly preferably at least 120% or more.
  • SEQ ID NO:1 reference protease
  • Washing or cleaning performance refers to the ability of a washing or cleaning agent to partially or completely remove existing soiling.
  • both the washing or cleaning agent comprising the protease or the washing or cleaning liquor formed by this agent, as well as the protease itself exhibit a respective cleaning performance.
  • the cleaning performance of the protease thus contributes to the cleaning performance of the agent or the washing or cleaning liquor formed by the agent.
  • washing or cleaning liquor refers to the working solution containing the washing or cleaning agent that acts on textiles or fabrics or hard surfaces, especially dishes, and thus comes into contact with the soiling present on the textiles or fabrics or hard surfaces, especially dishes.
  • the washing or cleaning liquor is usually created when the washing or cleaning process begins and the washing or cleaning agent is diluted with water, e.g., in a washing machine, dishwasher, or other suitable container.
  • the cleaning performance can be determined in a washing system containing a detergent at a dosage of between 2.0 and 8.0 grams per liter of wash liquor and the protease.
  • the proteases to be compared are used at the same concentration (based on active protein).
  • the protease concentration in the detergent intended for such a washing system is 0.001 to 0.1 wt.%, preferably 0.01 to 0.06 wt.%, based on active protein.
  • a liquid reference detergent for such a washing system can, for example, be composed as follows (all data in percent by weight (wt.%)): 4.4% alkylbenzenesulfonic acid, 5.6% other anionic surfactants, 2.4% C12-18 Na salts of fatty acids (soaps), 4.4% non-ionic surfactants, 0.2% phosphonates, 1.4% citric acid, 0.95% NaOH, 0.01% defoamers, 2% glycerol, 0.08% preservatives, 1% ethanol, and the remainder demineralized water.
  • the preferred dosage of the liquid detergent is between 4.5 and 6.0 grams per liter of wash liquor, e.g., 4.7, 4.9, or 5.9 grams per liter of wash liquor. Washing is preferably carried out in a pH range between pH 7 and pH 10.5, preferably between pH 8 and pH 9.
  • a liquid reference detergent for such a washing system should be composed as follows (all information in percent by weight): 0.3-0.5% xanthan gum, 0.2-0.4% anti-foam agent, 6-7% glycerin, 0.3-0.5% ethanol, 4-7% FAEOS (fatty alcohol ether sulfate), 5-15% non-ionic surfactants, 5-15% anionic surfactants (LAS), 1% boric acid, 1-4% sodium citrate (dihydrate), 2-4% soda, 2-6% coconut fatty acids, 0.5-2.5% HEDP (1-hydroxyethane-(1,1-di-phosphonic acid)), 0-0.4% PVP (polyvinylpyrrolidone), 0-0.15% optical brightener, 0-0.001% dye, balance demineralized water.
  • the dosage of the liquid detergent is preferably between 3.5 and 6.0 grams per liter of wash liquor, e.g., 4.7, 4.9, or 5.9 grams per liter of wash liquor. Washing is preferably carried out in a pH range between pH 8 and pH 10.5, preferably between pH 8 and pH 9.
  • a powdered reference detergent for such a washing system can be composed as follows (all data in percent by weight): 10% linear alkylbenzenesulfonate (sodium salt), 1.5% Ci2-18 fatty alcohol sulfate (sodium salt), 2.0% C s fatty alcohol with 7 EO, 20% sodium carbonate, 6.5% sodium hydrogen carbonate, 4.0% amorphous sodium disilicate, 17% sodium carbonate peroxohydrate, 4.0% TAED, 3.0% polyacrylate, 1.0% carboxymethylcellulose, 1.0% phosphonate, 27% sodium sulfate, remainder: foam inhibitors, optical brightener, perfumes.
  • the dosage of the powdered detergent is preferably between 4.5 and 7.0 grams per liter of wash liquor, e.g., and particularly preferably, 4.7 grams per liter of wash liquor, or 5.5, 5.9, or 6.7 grams per liter of wash liquor. Washing is preferably carried out in a pH range between pH 9 and pH 11.
  • the cleaning performance is determined for soiling on cotton by measuring the degree of cleaning of the washed textiles.
  • the washing process can be carried out for 60 minutes at a temperature of approximately 20°C or approximately 40°C, and the water can have a water hardness between 15.5°dH and 16.5°dH (German hardness).
  • the cleaning performance is determined, for example, at 20°C or 40°C using a liquid detergent as specified herein, with the washing process preferably being carried out for 60 minutes at 600 rpm.
  • the degree of whiteness i.e., the lightening of soils, as a measure of cleaning performance, is determined using optical measuring methods, preferably photometrically.
  • a suitable device for this purpose is the Minolta CM508d spectrometer. The devices used for the measurement are usually calibrated beforehand with a white standard, preferably one supplied with the product.
  • the cleaning performance of a dishwashing detergent can be determined in a system containing an automatic dishwashing detergent in a dosage as stated herein and the protease according to the invention, wherein the proteases to be compared are used at the same concentration (based on active protein) and the cleaning performance against a soiling of tea, meat, spaghetti and/or crèmekosée is determined according to the IKW method (Recommendations for the Quality Assessment of the Cleaning Performance of Dishwasher Detergents (Part B, Update 2015), sofwjournal, 142, 06/16, 34-48) in a Miele GSL (program 45°C, 21 °dH).
  • the concentration of the protease in the detergent intended for this washing system is 0.001 to 0.1 wt.%, preferably 0.01 to 0.06 wt.%, based on active, purified protein.
  • Liquid dishwashing detergent two-component formulation
  • the respective enzymes By using the respective enzymes with the same activity, it is ensured that even if there is a possible discrepancy in the ratio of active substance to total protein (the specific activity values), the respective enzymatic properties, such as the cleaning performance on specific soils, can be compared. Generally speaking, a low specific activity can be compensated by adding a larger amount of protein.
  • the enzymes to be tested can also be used in the same amount of substance or weight if the enzymes to be tested show a different affinity for the test substrate in an activity test.
  • equal weight refers to the use of the same weight of the enzymes being tested.
  • Preferred embodiments of proteases according to the invention achieve such advantageous cleaning performance even at low temperatures, in particular in the temperature ranges between about 20°C and about 75°C, preferably between about 30°C and about 60°C and particularly preferably between about 40°C and about 55°C.
  • protease activity can be determined via the release of the chromophore para-nitroaniline (pNA) from the substrate suc-L-Ala-L-Ala-L-Pro-L-Phe-p-nitroanilide (AAPF).
  • pNA chromophore para-nitroaniline
  • the protease cleaves the substrate and releases pNA.
  • the release of pNA causes an increase in absorbance at 410 nm, the time course of which is a measure of enzymatic activity (cf. Del Mar et al., 1979).
  • protease activity is usually expressed in protease units (PU). Suitable protease activities are, for example, 2.25, 5, or 10 PU per ml of wash liquor. However, protease activity is not zero.
  • An alternative test for determining the proteolytic activity of the proteases according to the invention is an optical measurement method, preferably a photometric method.
  • the test suitable for this purpose involves the protease-dependent cleavage of the substrate protein casein. This is cleaved by the protease into a multitude of smaller partial products. The totality of these partial products exhibits an increased absorption at 290 nm compared to non-cleaved casein. This increased absorption can be determined using a photometer, thus allowing conclusions to be drawn about the enzymatic activity of the protease.
  • the protein concentration can be determined using known methods, for example, the BCA method (bicinchoninic acid; 2,2'-biquinolyl-4,4'-dicarboxylic acid) or the biuret method (Gornall et al., J. Biol. Chem. 177, 1948, 751-766).
  • the determination of the active protein concentration can be achieved by titrating the active sites using a suitable irreversible inhibitor and determining the residual activity (cf. Bender et al., J. Am. Chem. Soc. 1966, 88, 24, 5890-5913).
  • the invention further relates to a protease as described herein, which is characterized in that it has at least one chemical modification.
  • a protease with such a modification is referred to as a derivative, i.e. the protease is derivatized.
  • Derivatives in the sense of the present application are understood to be proteins whose pure amino acid chain has been chemically modified. Such derivatizations can, for example, take place in vivo by the host cell expressing the protein. Coupling of low-molecular compounds such as lipids or oligosaccharides is particularly noteworthy in this regard.
  • Derivatizations can, however, also be carried out in vitro, for example by chemically converting a side chain of an amino acid or by covalently binding another Connection to the protein.
  • another Connection can also be another protein that is bound to a protein according to the invention, for example, via bifunctional chemical compounds.
  • Derivatization is also understood to mean covalent binding to a macromolecular carrier, or noncovalent inclusion in suitable macromolecular cage structures.
  • Derivatizations can, for example, influence the substrate specificity or the binding strength to the substrate, or temporarily block enzymatic activity if the coupled substance is an inhibitor. This can be useful, for example, for the storage period.
  • Such modifications can also influence stability or enzymatic activity. They can also serve to reduce the allergenicity and/or immunogenicity of the protein and thus, for example, increase its skin compatibility.
  • coupling with macromolecular compounds, e.g., polyethylene glycol can improve the protein in terms of stability and/or skin compatibility.
  • Derivatives of a protein according to the invention can, in the broadest sense, also be understood to include preparations of these proteins.
  • a protein can be combined with various other substances, e.g., from the culture of the producing microorganisms.
  • a protein can also be deliberately mixed with other substances, e.g., to increase its storage stability.
  • all preparations of a protein according to the invention are also according to the invention. This is independent of whether or not it actually exhibits this enzymatic activity in a particular preparation. It can be desired that it has no or only low activity during storage and only exhibits its enzymatic function at the time of use. This can be controlled, for example, via appropriate accompanying substances. In particular, the joint preparation of proteases with specific inhibitors is possible in this regard.
  • proteases or protease variants and/or derivatives described herein those whose storage stability and/or catalytic activity and/or substrate tolerance and/or purification performance is improved compared to a reference protease are particularly preferred within the scope of the present invention, wherein the catalytic activity and/or purification performance is determined as described herein.
  • the invention further relates to a nucleic acid encoding a protease according to the invention, as well as to a vector containing such a nucleic acid, in particular a cloning vector or an expression vector.
  • a nucleic acid encoding a protease according to the invention
  • a vector containing such a nucleic acid in particular a cloning vector or an expression vector.
  • These can be DNA or RNA molecules. They can be present as a single strand, as a single strand complementary to this single strand, or as a double strand.
  • the sequences of both complementary strands must be taken into account in all three possible reading frames.
  • different codons i.e., base triplets, can code for the same amino acids, so that a specific amino acid sequence can be encoded by several different nucleic acids.
  • nucleic acid sequences that can encode one of the proteases described above are included in this subject matter of the invention.
  • the skilled person is able to determine these nucleic acid sequences without any doubt, since, despite the degeneracy of the genetic code, defined amino acids can be assigned to individual codons. Therefore, the skilled person can Starting from an amino acid sequence, nucleic acids coding for this amino acid sequence can be easily determined.
  • nucleic acids according to the invention one or more codons can be replaced by synonymous codons.
  • This aspect relates in particular to the heterologous expression of the enzymes according to the invention. Thus, every organism, e.g. a host cell of a production strain, has a specific codon usage.
  • Codon usage is understood to mean the translation of the genetic code into amino acids by the respective organism. Bottlenecks in protein biosynthesis can arise if the codons on the nucleic acid in the organism are faced with a comparatively small number of loaded tRNA molecules. Although it encodes the same amino acid, this leads to a codon being translated less efficiently in the organism than a synonymous codon that encodes the same amino acid. Due to the presence of a higher number of tRNA molecules for the synonymous codon, it can be translated more efficiently in the organism.
  • vectors are understood to be elements consisting of nucleic acids which contain a nucleic acid according to the invention as a characteristic nucleic acid region. They are capable of establishing this nucleic acid as a stable genetic element in a species or cell line over several generations or cell divisions.
  • Vectors are special plasmids, i.e. circular genetic elements, particularly when used in bacteria.
  • a nucleic acid according to the invention is cloned into a vector.
  • Vectors include, for example, those whose origin is bacterial plasmids, viruses or bacteriophages, or predominantly synthetic vectors or plasmids with elements of various origins.
  • vectors are capable of establishing themselves as stable units in the respective host cells over several generations. They can exist extrachromosomally as independent units or integrate into a chromosome or chromosomal DNA.
  • Expression vectors comprise nucleic acid sequences that enable them to replicate in the host cells containing them, preferably microorganisms, particularly preferably bacteria, and to express a contained nucleic acid therein. Expression is influenced in particular by the promoter(s) that regulate transcription. In principle, expression can occur through the natural promoter originally located upstream of the nucleic acid to be expressed, but also through a promoter of the host cell provided on the expression vector, or through a modified or completely different promoter of another organism or another host cell.
  • At least one promoter for the expression of a nucleic acid according to the invention is provided and used for its expression.
  • Expression vectors can also be regulated, e.g., by changing the cultivation conditions or upon reaching a certain cell density of the nucleic acid containing them.
  • An example of such a substance is the galactose derivative isopropyl-ß-D-thiogalactopyranoside (IPTG), which is used as an activator of the bacterial lactose operon (lac operon).
  • IPTG galactose derivative isopropyl-ß-D-thiogalactopyranoside
  • lac operon lac operon
  • the invention further relates to a non-human host cell which comprises a nucleic acid according to the invention or a vector according to the invention, or which comprises a protease according to the invention, in particular one which secretes the protease into the medium surrounding the host cell.
  • a nucleic acid according to the invention or a vector according to the invention is transformed into a microorganism, which then represents a host cell according to the invention.
  • individual components i.e. nucleic acid parts or fragments of a nucleic acid according to the invention, can be introduced into a host cell in such a way that the resulting host cell contains a nucleic acid according to the invention or a vector according to the invention.
  • This procedure is particularly suitable when the host cell already contains one or more components of a nucleic acid according to the invention or a vector according to the invention, and the further components are then supplemented accordingly.
  • Methods for transforming cells are established in the prior art and sufficiently known to the person skilled in the art. In principle, all cells, i.e., prokaryotic or eukaryotic cells, are suitable as host cells.
  • Preferred host cells are those that are genetically advantageous to handle, for example, with regard to transformation with the nucleic acid or vector and its stable establishment, e.g., unicellular fungi or bacteria. Furthermore, preferred host cells are characterized by good microbiological and biotechnological handling.
  • Preferred host cells according to the invention secrete the (transgenically) expressed protein into the medium surrounding the host cells.
  • the proteases can be modified by the cells producing them after their production, e.g., by attaching sugar molecules, formylations, aminations, etc. Such post-translational modifications can influence the function of the protease.
  • host cells whose activity can be regulated by genetic regulatory elements, which are provided, for example, on the vector, but can also be present in these cells from the outset. These cells can be stimulated to express, for example, by controlled addition of chemical compounds that serve as activators, by changing the cultivation conditions, or upon reaching a certain cell density. This enables economical production of the proteins of the invention.
  • An example of such a compound is IPTG as described above.
  • Preferred host cells are prokaryotic or bacterial cells.
  • Bacteria are characterized by short generation times and low demands on cultivation conditions. This allows for the establishment of cost-effective cultivation methods or production processes.
  • the specialist in bacteria in fermentation technology has a rich A wealth of experience.
  • either gram-negative or gram-positive bacteria may be suitable for a variety of reasons, which must be determined experimentally in each individual case, such as nutrient sources, product formation rate, time required, etc.
  • gram-negative bacteria such as Escherichia coli, a large number of proteins are secreted into the periplasmic space, i.e. into the compartment between the two membranes surrounding the cells. This can be advantageous for special applications.
  • Gram-negative bacteria can also be engineered so that they secrete the expressed proteins not only into the periplasmic space, but also into the medium surrounding the bacterium.
  • Gram-positive bacteria such as Bacilli or Actinomycetes or other members of the Actinomycetes family, on the other hand, do not have an outer membrane, so that secreted proteins are immediately released into the medium surrounding the bacteria, usually the nutrient medium, from which the expressed proteins can be purified. They can be isolated directly from the medium or further processed.
  • Gram-positive bacteria are related to or identical to most of the source organisms for technically important enzymes and usually produce comparable enzymes themselves, so that they have a similar codon usage and their protein synthesis apparatus is naturally oriented accordingly.
  • Host cells according to the invention can be modified with regard to their requirements for culture conditions, have different or additional selection markers, or express different or additional proteins.
  • they can also be host cells that transgenically express several proteins or enzymes.
  • the present invention is in principle applicable to all microorganisms, in particular to all fermentable microorganisms, particularly preferably to those of the genus Bacillus, and leads to the production of proteins according to the invention through the use of such microorganisms. Such microorganisms then represent host cells within the meaning of the invention.
  • the host cell is characterized in that it is a bacterium, preferably one selected from the group of the genera Escherichia, Klebsiella, Bacillus, Staphylococcus, Corynebacterium, Arthrobacter, Streptomyces, Stenotrophomonas and Pseudomonas, more preferably one selected from the group of Escherichia coli, Klebsiella planticola, Bacillus licheniformis, Bacillus lentus, Bacillus amyloliquefaciens, Bacillus subtilis, Bacillus alcalophilus, Bacillus globigii, Bacillus gibsonii, Bacillus clausii, Bacillus halodurans, Bacillus pumilus, Staphylococcus carnosus, Corynebacterium glutamicum, Arthrobacter oxidans, Streptomyces lividans, Streptomyces coelicolor and Sten
  • the host cell can also be a eukaryotic cell, which is characterized by having a cell nucleus.
  • a further subject of the invention is therefore a host cell characterized by having a cell nucleus.
  • eukaryotic cells are capable of post-translationally modifying the protein they produce. Examples of this are fungi such as actinomycetes or yeasts such as Saccharomyces or Kluyveromyces. This can be particularly advantageous, for example, if the proteins are to undergo specific modifications in connection with their synthesis, which enable such systems.
  • the modifications that eukaryotic systems carry out, particularly in connection with protein synthesis include the binding of low-molecular-weight compounds such as membrane anchors or oligosaccharides.
  • Such oligosaccharide modifications can, for example, be used to reduce allergenicity. of an expressed protein may be desirable. Co-expression with enzymes naturally produced by such cells, such as cellulases, may also be advantageous. Furthermore, thermophilic fungal expression systems, for example, may be particularly suitable for the expression of temperature-stable proteins or variants.
  • the host cells according to the invention are cultivated and fermented in a conventional manner, e.g., in discontinuous or continuous systems.
  • a suitable nutrient medium is inoculated with the host cells, and the product is harvested from the medium after a period of time to be determined experimentally.
  • Continuous fermentations are characterized by the achievement of a steady state in which cells partially die but also regrow over a comparatively long period of time, and the formed protein can be simultaneously extracted from the medium.
  • Host cells according to the invention are preferably used to produce proteases according to the invention.
  • the invention therefore further provides a process for producing a protease comprising a) culturing a host cell according to the invention, and b) isolating the protease from the culture medium or from the host cell.
  • This subject matter of the invention preferably comprises fermentation processes.
  • Fermentation processes are known per se from the prior art and represent the actual large-scale production step, usually followed by a suitable purification method for the manufactured product, e.g., the proteases according to the invention. All fermentation processes based on a corresponding process for producing a protease according to the invention represent embodiments of this subject matter of the invention. Fermentation processes characterized in that the fermentation is carried out via a feed strategy are particularly suitable. Here, the media components consumed by the ongoing cultivation are fed in. This allows significant increases in both cell density and cell mass or dry mass and/or, in particular, in the activity of the protease of interest to be achieved. Furthermore, the fermentation can also be designed such that unwanted metabolic products are filtered out or neutralized by adding buffer or appropriate counterions.
  • the produced protease can be harvested from the fermentation medium.
  • Such a fermentation process is preferable to isolating the protease from the host cell, i.e., product preparation from the cell mass (dry mass), but requires the provision of suitable host cells or one or more suitable secretion markers or mechanisms and/or transport systems to ensure that the host cells secrete the protease into the fermentation medium.
  • the protease can alternatively be isolated from the host cell, i.e., purified from the cell mass, e.g., by precipitation with ammonium sulfate or ethanol, or by chromatographic purification.
  • the invention further provides an agent characterized in that it contains a protease according to the invention as described herein.
  • the agent is preferably a washing and cleaning agent, in particular a washing and cleaning agent containing bleach, preferably a dishwasher detergent, particularly preferably a dishwasher detergent containing bleach.
  • proteases according to the invention are used in washing or cleaning agents, in particular dishwasher detergents, which contain at least one bleaching agent preparation.
  • the bleaching agent preparation comprises an oxygen bleaching agent selected from the group consisting of hydrogen peroxide, peroxomonosulfate salts, peroxodisulfate salts and phthalimidoperoxohexanoic acid (PAP), wherein the weight fraction of the oxygen bleaching agent in the total weight of the bleaching agent preparation is preferably between 0.1 and 50 wt.%, preferably between 0.2 and 35 wt.%, particularly preferably between 0.5 and 20 wt.% and in particular between 1.0 and 10 wt.%.
  • PAP phthalimidoperoxohexanoic acid
  • the bleaching agent preparation comprises an oxidizing agent.
  • the oxidizing agent is preferably selected from chlorine dioxide, calcium hypochlorite, potassium hypochlorite, sodium hypochlorite.
  • the bleaching agent preparation comprises sodium hypochlorite as oxidizing agent.
  • the bleaching agent composition contains the at least one oxidizing agent, preferably the alkali metal hypochlorite, in particular sodium hypochlorite, in amounts of 0.1 to 8.0 wt. %, preferably 0.15 to 3.0 wt. %, and more preferably 0.2 to 1.0 wt. %, based on the total weight of the bleaching agent preparation.
  • bleaching agents include peroxypyrophosphates, citrate perhydrates, and H2O2-yielding peracidic salts or peracids, such as perbenzoates, peroxophthalates, diperazelaic acid, phthaloiminoperacid, or diperdodecanedioic acid.
  • bleaching agents from the group of organic bleaching agents can also be used.
  • Typical organic bleaching agents are diacyl peroxides, such as dibenzoyl peroxide.
  • Other typical organic bleaching agents are peroxyacids, with alkyl peroxyacids and aryl peroxyacids being particularly mentioned as examples.
  • the washing or cleaning agent in particular automatic dishwashing agent, comprises at least one bleach catalyst from the group of transition metal catalysts.
  • These substances are preferably bleach-enhancing transition metal salts or transition metal complexes, such as Mn, Fe, Co, Ru, or Mo salen complexes or carbonyl complexes.
  • Mn, Fe, Co, Ru, Mo, Ti, V, and Cu complexes with N-containing tripod ligands, as well as Co, Fe, Cu, and Ru ammine complexes can also be used as bleach catalysts.
  • complexes of manganese in oxidation state II, III, IV, or IV which preferably contain one or more macrocyclic ligands with the donor functions N, NR, PR, O, and/or S.
  • bleach catalyst(s) in the agents according to the invention which contain 1,4,7-trimethyl-1,4,7-triazacyclononane (Me-TACN), 1,4,7-triazacyclononane (TACN), 1,5,9-trimethyl-1,5,9-triazacyclododecane (Me-TACD), 2-methyl-1,4,7-trimethyl-1,4,7-triazacyclononane (Me/Me-TACN) and/or 2-methyl-1,4,7-triazacyclononane (Me/TACN) as macromolecular ligands.
  • the weight fraction of the bleach catalyst in the total weight of the washing or cleaning agent is preferably 0.001 to 2.0 wt.%, preferably 0.001 to 1.0 wt.% and in particular 0.001 to 0.5 wt.%.
  • Dishwashing detergents according to the invention may further contain bleach activators, e.g., to achieve an improved bleaching effect when cleaning at temperatures of 60°C and below.
  • bleach activators e.g., to achieve an improved bleaching effect when cleaning at temperatures of 60°C and below.
  • Compounds that, under perhydrolysis conditions, yield aliphatic peroxocarboxylic acids having preferably 1 to 10 carbon atoms, in particular 2 to 4 carbon atoms, and/or optionally substituted perbenzoic acid can be used as bleach activators.
  • Suitable substances are those that carry O- and/or N-acyl groups with the stated number of carbon atoms and/or optionally substituted benzoyl groups.
  • Polyacylated alkylenediamines are preferred, with tetraacetylethylenediamine (TAED) having proven particularly suitable.
  • bleach activators in particular TAED, are preferably used in amounts of 0.1 to 10 wt.%, in particular 0.1 to 8 wt.%, particularly 2 to 8 wt.% and particularly preferably 2 to 6 wt.%, based on the total weight of the agent.
  • washing or cleaning agents in particular dishwasher detergents, which each comprise, based on the total weight of the agent:
  • (C) optionally at least one bleach catalyst, preferably in an amount of 0.001 to 2.0 wt.% and increasingly preferably from 0.001 to 1.0 wt.% or 0.001 to 0.5 wt.%, and
  • washing or cleaning agents in particular dishwasher detergents, which each comprise, based on the total weight of the agent:
  • washing or cleaning agents in particular dishwasher detergents, which each comprise, based on the total weight of the agent:
  • the protease according to the invention is used in agents that are essentially free of boron-containing compounds.
  • "Essentially free of boron-containing compounds” in this context means that the agents according to the invention contain less than 2% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and particularly preferably less than 0.1% by weight, of boron-containing compounds, based on the total weight of the agent.
  • the washing and cleaning agents according to the invention are free of boron-containing compounds, i.e., they contain, in particular, no boric acid and/or phenylboronic acid derivatives.
  • the protease according to the invention is used in agents that are essentially free of phosphonate-containing compounds.
  • Essentially free of phosphonate-containing compounds in this context means that the agents according to the invention contain less than 2% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and particularly preferably less than 0.1% by weight, of phosphonate-containing compounds, based on the total weight of the agent. In particularly preferred embodiments, these agents are free of phosphonate-containing compounds.
  • the protease according to the invention is used in agents that are essentially free of phosphate-containing compounds.
  • "Essentially free of phosphate-containing compounds” in this context means that the agents according to the invention contain less than 2% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and particularly preferably less than 0.1% by weight, of phosphate-containing compounds, based on the total weight of the agent. In particularly preferred embodiments, these agents are free of phosphate-containing compounds.
  • a washing or cleaning agent is understood to mean all conceivable types of washing or cleaning agents, both concentrated and undiluted, for use on a commercial scale, in a washing machine or for hand washing or cleaning.
  • This includes, for example, washing agents for textiles, carpets, or natural fibers, for which the term washing agent is used.
  • This also includes, for example, dishwashing detergents for dishwashers (machine dishwashing detergents) or manual dishwashing detergents or cleaners for hard surfaces such as metal, glass, porcelain, ceramics, tiles, stone, painted surfaces, plastics, wood, or leather, for which the term cleaning agent is used, i.e., in addition to manual and machine dishwashing detergents, scouring agents, glass cleaners, toilet air fresheners, etc.
  • washing and cleaning agents within the scope of the invention also include washing aids that are added to the actual washing agent during manual or machine textile washing to achieve an additional effect.
  • cleaning agents also include textile pre- and post-treatment agents, i.e., agents with which the laundry is brought into contact before the actual washing process, e.g., to loosen stubborn dirt, and also agents that, in a step following the actual textile washing process, impart further desirable properties to the laundry, such as a pleasant feel, crease resistance, or low static charge.
  • Fabric softeners are considered to be among the latter agents.
  • the washing or cleaning agents according to the invention which can be in the form of powdered or granular solids, in compacted or recompacted particle form, as homogeneous solutions or suspensions, can contain, in addition to a protease according to the invention, all known ingredients customary in such agents, with at least one further ingredient preferably being present in the agent.
  • the agents according to the invention can contain, in particular, surfactants, builders, polymers, glass corrosion inhibitors, corrosion inhibitors, bleaching agents such as peroxygen compounds, bleach activators or bleach catalysts.
  • compositions according to the invention can also contain water-miscible organic solvents, other enzymes, enzyme stabilizers, sequestering agents, electrolytes, pH regulators and/or other auxiliaries such as optical brighteners, graying inhibitors, dye transfer inhibitors, foam regulators, dyes and fragrances, and combinations thereof.
  • Advantageous ingredients of the compositions according to the invention are disclosed in the international patent application WO 2009/121725, beginning on page 5, penultimate paragraph, and ending on page 13 after the second paragraph. This disclosure is expressly incorporated by reference, and the disclosure content therein is incorporated into the present patent application.
  • An agent according to the invention advantageously contains the protease according to the invention in an amount of 2 pg to 20 mg, preferably 5 pg to 17.5 mg, particularly preferably 20 pg to 15 mg, and most preferably 50 pg to 10 mg per g of the agent.
  • the concentration of the protease described herein (active enzyme) in the agent is >0 to 1 wt.%, preferably 0.0001 or 0.001 to 0.1 wt.%, based on the total weight of the agent or composition.
  • An agent according to the invention increasingly preferably contains the protease in an amount of 1 x 10 -8 to 5 wt.%, from 0.0001 to 1 wt.%, from 0.0005 to 0.5 wt.%, from 0.001 to 0.1 wt.%, in each case based on active protein and based on the total weight of the detergent.
  • the embodiments of the present invention encompass all solid, powdered, liquid, gel-like, or pasty dosage forms of agents according to the invention, which may optionally also consist of several phases and may be present in compressed or uncompressed form.
  • the agent may be in the form of a free-flowing powder, in particular with a bulk density of 300 g/l to 1200 g/l, in particular 500 g/l to 900 g/l or 600 g/l to 850 g/l.
  • Solid dosage forms of the agent also include extrudates, granules, tablets, or pouches.
  • the agent may also be liquid, gel-like, or pasty, e.g., in the form of a non-aqueous liquid detergent or a non-aqueous paste, or in the form of an aqueous liquid detergent or a water-containing paste.
  • Liquid agents are generally preferred.
  • the agent may be in the form of a one-component system. Such agents consist of a Phase.
  • a remedy can also consist of several phases. Such a remedy is therefore divided into several components.
  • the proteases according to the invention are preferably used in automatic dishwashing detergents, in particular automatic dishwashing detergents containing bleach, for cleaning hard surfaces, in particular dishes.
  • Detergents or cleaning agents according to the invention can contain exclusively one protease according to the invention. Alternatively, they can also contain further hydrolytic enzymes or other enzymes in a concentration appropriate for the effectiveness of the agent. A further embodiment of the invention thus represents agents which further comprise one or more further enzymes.
  • enzymes which can exhibit catalytic activity in the agent according to the invention, in particular a lipase, amylase, cellulase, hemicellulase, mannanase, tannase, xylanase, xanthanase, xyloglucanase, ß-glucosidase, pectinase, carrageenase, perhydrolase, oxidase, oxidoreductase or other proteases distinguishable from the proteases according to the invention, as well as mixtures thereof.
  • each further enzyme is contained in agents according to the invention in an amount of 1 x 10 -7 to 3 wt.%, from 0.00001 to 1 wt.%, from 0.00005 to 0.5 wt.%, from 0.0001 to 0.1 wt.% and particularly preferably from 0.0001 to 0.05 wt.%, based on active protein.
  • the enzymes particularly preferably display synergistic cleaning performance against certain soilings or stains, i.e. the enzymes contained in the agent mutually support each other in their cleaning performance.
  • synergism very particularly preferably exists between the protease contained according to the invention and another enzyme in an agent according to the invention. Synergistic effects can occur not only between different enzymes, but also between one or more enzymes and other ingredients of the agent according to the invention.
  • Dishwashing detergents preferred according to the invention comprise at least one protease and at least one amylase.
  • Textile detergents preferred according to the invention comprise at least one protease and at least one amylase.
  • textile detergents comprise at least one protease and at least one cellulase.
  • textile detergents comprise at least one protease and at least one lipase.
  • textile detergents comprise at least one protease, at least one amylase, and at least one lipase.
  • textile detergents comprise at least one protease, at least one amylase, and at least one cellulase.
  • textile detergents comprise at least one protease, at least one amylase, at least one cellulase, and at least one lipase.
  • proteases are the subtilisins BPN' from Bacillus amyloliquefaciens and Carlsberg from Bacillus licheniformis, the protease PB92, the subtilisins 147 and 309, the protease from Bacillus lentus, subtilisin DY and the subtilases, but no longer the subtilisins in the narrower sense
  • Subtilisin Carlsberg is available in a further developed form under the trade name Alcalase® from Novozymes.
  • Subtilisins 147 and 309 are marketed by Novozymes under the trade names Esperase® and Savinase®, respectively.
  • Protease variants are derived from the protease from Bacillus lentus DSM 5483, described in e.g. WO 95/23221, WO 92/21760, WO 2013/060621 and EP 3660151.
  • proteases are, for example, those sold under the trade names Durazym®, Relase®, Everlase®, Nafizym®, Kannase®, Progress Uno 101 L® and Ovozyme® by Novozymes, those sold under the trade names Purafect®, Purafect® OxP, Purafect® Prime, Excellase®, Properase®, Preferenz P100® and Preferenz P300® by Danisco/DuPont, those sold under the trade name Lavergy pro 104 LS® by BASF, those sold under the trade name Protosol® by Advanced Biochemicals Ltd., those sold under the trade name Wuxi® from Wuxi Snyder Bioproducts Ltd., the enzymes available under the trade names Proleather® and Protease P® from Amano Pharmaceuticals Ltd., and the enzyme available under the name Proteinase K-16 from Kao Corp.
  • proteases from Bacillus gibsonii and Bacillus pumilus which are disclosed in WO 2008/086916, WO 2007/131656, WO 2017/215925, WO 2021/175696 and WO 2021/175697, are also particularly preferably used.
  • Other usable proteases are those that are naturally present in the microorganisms Stenotrophomonas maltophilia, in particular Stenotrophomonas maltophilia K279a, Bacillus intermedius and Bacillus sphaericus.
  • amylases are the ⁇ -amylases from Bacillus licheniformis, Bacillus amyloliquefaciens or Bacillus stearothermophilus and, in particular, their further developments improved for use in detergents or cleaning agents.
  • the enzyme from Bacillus licheniformis is available from Novozymes under the name Termamyl® and from Danisco/DuPont under the name Purastar® ST. Further developments of this ⁇ -amylase are available under the trade names Duramyl® and Termamyl® ultra (both from Novozymes), Purastar® OxAm (Danisco/DuPont) and Keistase® (Daiwa Seiko Inc.).
  • the ⁇ -amylase from Bacillus amyloliquefaciens is marketed by Novozymes under the name BAN®, and derived variants of the ⁇ -amylase from Bacillus stearothermophilus under the names BSG® and Novamyl®, also from Novozymes.
  • Other suitable enzymes for this purpose include ⁇ -amylase from Bacillus sp. A 7-7 (DSM 12368) and cyclodextrin glucanotransferase (CGTase) from Bacillus agaradherens (DSM 9948). Fusion products of all of these molecules can also be used.
  • ⁇ -amylase from Aspergillus niger and A are marketed by Novozymes under the name BAN®, and derived variants of the ⁇ -amylase from Bacillus stearothermophilus under the names BSG® and Novamyl®, also from Novozymes.
  • Other suitable enzymes for this purpose include ⁇ -
  • oryzae available under the trade name Fungamyl® from Novozymes, are also suitable.
  • Other commercial products that can be used advantageously include Amylase-LT® and Stainzyme® or Stainzyme® ultra or Stainzyme® plus, as well as AmplifyTM 12L, Amplify PrimeTM 120L, or Amplify PrimeTM 100L, the latter also from Novozymes, and the PREFERENZ S® series from Danisco/DuPont, including PREFERENZ S100®, PREFERENZ S1000®, or PREFERENZ S210®. Variants of these enzymes obtainable through point mutations can also be used according to the invention.
  • Suitable cellulases include those of bacterial or fungal origin.
  • Suitable cellulases are cellulases from the genera Bacillus, Pseudomonas, Humicola, Fusarium, Thielavia, and Acremonium, e.g., the fungal cellulases from Humicola insolens, Myceliophthora thermophila, and Fusarium oxysporum, disclosed in US 4,435,307, US 5,648,263, US 5,691,178, US 5,776,757, and WO 89/09259. Particularly suitable cellulases are alkaline or neutral cellulases with color-care properties.
  • cellulases examples include cellulases described in EP 0495257, EP 0531372, WO 96/11262, WO 96/29397 and WO 98/08940.
  • Examples of cellulases with endo-1,4-glucanase activity are described in WO 2002/099091, e.g., those with a sequence of at least 97% identity to the amino acid sequence of positions 1 to 773 of SEQ ID NO:2 of WO 2002/099091.
  • Another example may comprise a GH44 xyloglucanase, e.g., a xyloglucanase enzyme with a sequence of at least 60% identity to positions 40 to 559 of SEQ ID NO:2 of WO 2001/062903.
  • a GH44 xyloglucanase e.g., a xyloglucanase enzyme with a sequence of at least 60% identity to positions 40 to 559 of SEQ ID NO:2 of WO 2001/062903.
  • Commercially available cellulases include CelluzymeTM, CarezymeTM, Carezyme PremiumTM, CellucleanTM (e.g.
  • CellucleanTM 5000L and CellucleanTM 4000T Celluclean ClassicTM, CellusoftTM, Endolase®, Renozyme® and WhitezymeTM (Novozymes A/S), ClazinaseTM and Puradax HATM (Genencor International Inc.), KAC-500(B)TM (Kao Corporation), RevitalenzTM 1000, RevitalenzTM 2000 and RevitalenzTM 3000 (DuPont), as well as Ecostone® and Biotouch® (AB Enzymes).
  • lipases or cutinases particularly because of their triglyceride-cleaving activities, but also to generate peracids from suitable precursors in situ.
  • Suitable lipases and cutinases are those of bacterial or fungal origin. Chemically modified or mutated enzymes produced by protein engineering are included. Examples are lipase from Thermomyces, e.g. from T. lanuginosus (formerly called Humicola lanuginosa), as described in EP 0258068 and EP 0305216, cutinase from Humicola, e.g. H.
  • insolens (WO 96/13580), lipase from strains of Pseudomonas (some of which have now been renamed Burkholderia), e.g. P. alcaligenes or P. pseudoalcaligenes, P. cepacia, P. sp. Strain SD705, P.
  • Preferred lipases include, for example, those originally obtainable from Humicola lanuginosa (Thermomyces lanuginosus) or developed therefrom, in particular those with one or more of the following amino acid substitutions starting from the aforementioned lipase at positions D96L, T213R, and/or N233R, particularly preferably T213R and N233R.
  • Preferred commercial lipase products include LipolaseTM, LipexTM, LipolexTM and LipocleanTM (Novozymes A/S), Lumafast (Genencor/DuPont) and Lipomax (Gist-Brocades).
  • oxidoreductases e.g., oxidases, oxygenases, catalases, peroxidases, such as halo-, chloro-, bromo-, lignin-, glucose- or manganese peroxidases, dioxygenases or laccases (phenol oxidases, polyphenol oxidases)
  • organic compounds, particularly aromatic ones, which interact with the enzymes are additionally added in order to increase the activity of the oxidoreductases in question (enhancers) or to Redox potentials between the oxidizing enzymes and the soils to ensure the flow of electrons (mediators).
  • the enzymes to be used can also be formulated together with accompanying substances, such as those from fermentation.
  • the enzymes are preferably used as liquid enzyme formulation(s).
  • the enzymes are generally not provided in the form of pure protein, but rather in the form of stabilized, storable, and transportable preparations.
  • These prefabricated preparations include, for example, solid preparations obtained by granulation, extrusion, or lyophilization or, particularly in the case of liquid or gel-like products, solutions of the enzymes, preferably as concentrated as possible, with little water content, and/or containing stabilizers or other additives.
  • the enzymes can be encapsulated for both solid and liquid dosage forms, e.g., by spray-drying or extrusion of the enzyme solution together with a preferably natural polymer, or in the form of capsules, e.g., those in which the enzymes are enclosed as if in a solidified gel, or in core-shell capsules, in which an enzyme-containing core is coated with a water-, air-, and/or chemical-impermeable protective layer.
  • Additional active ingredients e.g., stabilizers, emulsifiers, pigments, bleaching agents, or dyes, can be applied in superimposed layers.
  • Such capsules are applied using conventional methods, e.g., by shaking or rolling granulation or in fluid-bed processes.
  • Such granules, e.g., by applying polymeric film-forming agents are advantageously low in dust and, due to the coating, are storage-stable.
  • water-soluble films such as those used in the packaging of unit-dose detergents and cleaning agents.
  • Such a film allows the enzymes to be released upon contact with water.
  • water-soluble refers to a film structure that is preferably completely water-soluble.
  • a film consists of (fully or partially hydrolyzed) polyvinyl alcohol (PVA).
  • the invention further relates to a method for cleaning textiles and/or hard surfaces, in particular tableware, which is characterized in that an agent according to the invention is used in at least one method step.
  • the described method is characterized in that the protease is used at a temperature of about 0°C to about 100°C, preferably about 20°C to about 75°C, more preferably about 30°C to about 60°C, and particularly preferably about 40°C to about 55°C.
  • Textile cleaning processes are generally characterized by the fact that various cleaning-active substances are applied to the fabric in several process steps. applied to the item to be cleaned and washed off after the exposure time, or that the item to be cleaned is treated in any other way with a detergent or a solution or dilution of this agent.
  • a single and/or the only step of such a process can consist of bringing a protease according to the invention into contact with the soil as the sole cleaning-active component, preferably in a buffer solution or in water. This represents a further embodiment of this subject matter of the invention.
  • Alternative embodiments of this subject matter of the invention also include processes for treating textile raw materials or for textile care, in which a protease according to the invention is activated in at least one process step.
  • processes for textile raw materials, fibers, or textiles with natural components are preferred, and especially for those containing wool or silk.
  • Another subject of the invention relates to a method for cleaning textiles and/or hard surfaces, in particular dishes, wherein in at least one method step a washing or cleaning agent which contains a protease according to the invention as described herein and/or a protease according to the invention as described herein is used.
  • the invention also encompasses the use of proteases according to the invention, as described herein, in washing or cleaning agents, in particular washing or cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, for cleaning textiles and/or hard surfaces, in particular dishes.
  • the present invention relates to an alkaline protease of the subtilisin type from Bacillus gibsonii.
  • Variants of this protease wild type: Bacillus gibsonii protease according to SEQ ID NO:1 were produced by random mutagenesis, which were then screened for, among other things, improved washing performance and/or improved enzyme stability.
  • the protease variants mentioned herein were generated from the above-mentioned wild-type protease (SEQ ID NO:1) by random mutagenesis and/or saturation mutagenesis. Furthermore, some mutants were produced by targeted generation of synthetic genes.
  • protease variants The recombinant expression of the protease variants according to the invention was carried out according to methods described in the literature (Vojcic et al., An efficient transformation method for Bacillus subtilis DB104, Appl Microbiol Biotechnol, 2012, 94 (2): 487-493).
  • the activity of the protease is determined by the release of the chromophore para-nitroaniline from the substrate succinyl alanine-alanine-proline-phenylalanine-para-nitroanilide (AAPFpNA; Bachem L-1400).
  • AAPFpNA succinyl alanine-alanine-proline-phenylalanine-para-nitroanilide
  • the measurement was carried out at a temperature of 25°C, at pH 8.6 and a wavelength of 410 nm.
  • the measurement time was 5 min with a measurement interval of 20 to 60 seconds.
  • a protease solution which causes an absorbance change of 0.500 OD under these conditions has, according to the current designation, an activity of 10 HPE per ml (cf. e.g. Schülein et al., Mol Gen Gent (1991) 227:137-143).
  • protease variants listed in Table 1 were added to a wash liquor containing various active chlorine concentrations and incubated for 30 min at 30°C. The reaction was stopped with 2% Na sulfite (40 ml / 2 ml) and the protease activity was determined using AAPF (see Example 2).
  • a 5,000 ppm active chlorine stock solution in detergent matrix was prepared according to Table 2 and the pH was adjusted to pH 8 with 2M HCl.
  • protease-containing samples and control samples were treated with various concentrations of active chlorine (0 ppm, 0.5 ppm, 1 ppm, 2 ppm, 4 ppm, 10 ppm).
  • the samples were stirred for 30 s and then incubated in a water bath for 30 min at 30°C. After incubation, 2% sodium sulfite (40 mg/2 ml) was added to inactivate the active chlorine.
  • the samples were mixed and stored on ice until analysis.
  • the protease activity (determined according to Example 2) of the respective proteases is shown in Table 3.
  • the activity of the respective protease after incubation for 30 min at 30°C without the addition of active chlorine was normalized to 100%.
  • protease variants according to the invention show significantly improved stability towards sodium hypochlorite compared to the wild type (P1).
  • proteases according to the invention exhibit improved cleaning performance compared to the wild type (P1).
  • proteases according to the invention can be used in various washing and cleaning compositions and realize their effect.

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Abstract

The invention relates to proteases which have proteolytic activity and comprise an amino acid sequence which is at least 70% and increasingly preferably at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5% and 98% identical to the amino acid sequence indicated in SEQ ID NO:1 over its entire length, wherein the protease, with respect to the numbering according to SEQ ID NO: 1, (i) has at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S at at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, and (ii) has at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L and Q256E at at least one of the positions corresponding to positions 29, 58, 89, 117 and 216. The invention also relates to a washing or cleaning agent, in particular bleach-containing washing or cleaning agent, preferably machine dishwashing agent, particularly preferably bleach-containing machine dishwashing agent, comprising a protease according to the invention.

Description

PROTEASE-VARIANTEN MIT VERBESSERTER BLEICHESTABILITÄT PROTEASE VARIANTS WITH IMPROVED BLEACH STABILITY

Die Erfindung liegt auf dem Gebiet der Enzymtechnologie. Die Erfindung betrifft Proteasen, deren Aminosäuresequenz insbesondere im Hinblick auf den Einsatz in Wasch- und Reinigungsmitteln, insbesondere im Hinblick auf Maschinengeschirrspülmittel, verändert wurden, um ihre Stabilität, insbesondere ihre Stabilität in Gegenwart von Bleichmittel, zu verbessern, und die für sie codierende Nukleinsäuren sowie deren Herstellung. Die Erfindung betrifft ferner die Verwendungen dieser Proteasen und Verfahren, in denen sie eingesetzt werden, sowie diese enthaltende Wasch- und Reinigungsmittel, insbesondere bleichmittelhaltige Wasch- und Reinigungsmittel, bevorzugt Maschinengeschirrspülmittel, besonders bevorzugt bleichmittelhaltige Maschinengeschirrspülmittel. The invention lies in the field of enzyme technology. The invention relates to proteases whose amino acid sequence has been modified, particularly with regard to use in detergents and cleaning agents, in particular with regard to automatic dishwashing detergents, in order to improve their stability, in particular their stability in the presence of bleach, and to the nucleic acids encoding them and their preparation. The invention further relates to the uses of these proteases and methods in which they are used, as well as to detergents and cleaning agents containing them, in particular detergents and cleaning agents containing bleach, preferably automatic dishwashing detergents, particularly preferably automatic dishwashing detergents containing bleach.

Proteasen gehören zu den technisch bedeutendsten Enzymen überhaupt. Für Wasch- und Reinigungsmittel sind sie die am längsten etablierten und in praktisch allen modernen, leistungsfähigen Wasch- und Reinigungsmitteln enthaltenen Enzyme. Sie bewirken den Abbau proteinhaltiger Anschmutzungen auf dem Reinigungsgut. Hierunter sind wiederum Proteasen vom Subtilisin-Typ (Subtilasen, Subtilopeptidasen, EC 3.4.21.62) besonders wichtig, welche aufgrund der katalytisch wirksamen Aminosäuren Serin-Proteasen sind. Sie wirken als unspezifische Endopeptidasen und hydrolysieren beliebige Säureamidbindungen, die im Inneren von Peptiden oder Proteinen liegen. Ihr pH-Optimum liegt meist im deutlich alkalischen Bereich. Einen Überblick über diese Familie bietet z.B. der Artikel "Subtilases: Subtilisin-Iike Proteases" von R. Siezen, Seiten 75-95 in "Subtilisin enzymes", herausgegeben von R. Bott und C. Betzel, New York, 1996. Subtilasen werden natürlicherweise von Mikroorganismen gebildet. Hierunter sind insbesondere die von Bacillus- Spezies gebildeten und sezernierten Subtilisine als bedeutendste Gruppe innerhalb der Subtilasen zu erwähnen. Proteases are among the most technically important enzymes of all. They are the longest-established enzymes in detergents and cleaning agents and are contained in virtually all modern, high-performance detergents and cleaning agents. They break down protein-containing soils on the items being cleaned. Among these, proteases of the subtilisin type (subtilases, subtilopeptidases, EC 3.4.21.62) are particularly important. These are serine proteases due to the catalytically active amino acids. They act as nonspecific endopeptidases and hydrolyze any acid amide bonds found within peptides or proteins. Their pH optimum is usually in the significantly alkaline range. An overview of this family is provided, for example, in the article "Subtilases: Subtilisin-like Proteases" by R. Siezen, pages 75-95 in "Subtilisin Enzymes," edited by R. Bott and C. Betzel, New York, 1996. Subtilases are naturally produced by microorganisms. Among them, the subtilisins, produced and secreted by Bacillus species, are particularly noteworthy as the most important group within the subtilases.

Beispiele für die in Wasch- und Reinigungsmitteln bevorzugt eingesetzten Proteasen vom Subtilisin-Typ sind die Subtilisine BPN' und Carlsberg, die Protease PB92, die Subtilisine 147 und 309, die alkalische Protease aus Bacillus lentus, insbesondere aus Bacillus lentus DSM 5483, Subtilisin DY und die den Subtilasen, nicht mehr jedoch den Subtilisinen im engeren Sinne zuzuordnenden Enzyme Thermitase, Proteinase K und die Proteasen TW3 und TW7, sowie Varianten der genannten Proteasen, die eine gegenüber der Ausgangsprotease veränderte Aminosäuresequenz aufweisen. Proteasen werden durch aus dem Stand der Technik bekannte Verfahren gezielt oder zufallsbasiert verändert und so z.B. für den Einsatz in Wasch- und Reinigungsmitteln optimiert. Dazu gehören Punkt-, Deletions- oder Insertionsmutagenese oder Fusion mit anderen Proteinen oder Proteinteilen. So sind für die meisten aus dem Stand der Technik bekannten Proteasen entsprechend optimierte Varianten bekannt. In WO 2017/215925 ist z.B. eine für Wasch- und Reinigungsmittel vorgesehene Protease aus Bacillus gibsonii bzw. Varianten davon offenbart. Examples of the subtilisin-type proteases preferably used in detergents and cleaning agents are the subtilisins BPN' and Carlsberg, the protease PB92, the subtilisins 147 and 309, the alkaline protease from Bacillus lentus, in particular from Bacillus lentus DSM 5483, subtilisin DY, and the enzymes thermitase, proteinase K, and the proteases TW3 and TW7, which are classified as subtilases but no longer as subtilisins in the narrower sense, as well as variants of the aforementioned proteases that have an amino acid sequence that is altered compared to the parent protease. Proteases are modified in a targeted or random manner using methods known from the state of the art and thus optimized, for example, for use in detergents and cleaning agents. These include point, deletion, or insertion mutagenesis, or fusion with other proteins or protein fragments. For most of the proteases known from the state of the art, optimized variants are known. WO 2017/215925, for example, discloses a protease from Bacillus gibsonii or variants thereof intended for use in detergents and cleaning agents.

Generell sind nur ausgewählte Proteasen für den Einsatz in tensid- und/oder bleichmittelhaltigen Zubereitungen überhaupt geeignet. Viele Proteasen zeigen in derartigen Zubereitungen keine ausreichende katalytische Leistung oder aber sie sind nicht ausreichend stabil. Für die Anwendung von Proteasen in Wasch- und Reinigungsmitteln ist daher eine hohe katalytische Aktivität und Stabilität unter Bedingungen, wie sie sich während eines Wasch- oder Reinigungsvorgangs darstellen, besonders wünschenswert. Folglich haben protease- und tensid- und/oder bleichmittelhaltige Formulierungen aus dem Stand der Technik den Nachteil, dass die enthaltenen Proteasen unter Standardwasch- und/oder -reinigungsbedingungen keine zufriedenstellende proteolytische Aktivität aufweisen und/oder nicht ausreichend stabil sind, und die Formulierungen daher keine optimale Reinigungsleistung an proteasesensitiven Anschmutzungen zeigen. Proteasesensitive Anschmutzungen sind vorzugsweise aus der aus blut-, ei(gelb)-, milch- und anderen proteinhaltigen Anschmutzungen bestehenden Gruppe ausgewählt. Generally, only selected proteases are suitable for use in preparations containing surfactants and/or bleaching agents. Many proteases do not show any sufficient catalytic performance or they are not sufficiently stable. For the use of proteases in washing and cleaning agents, high catalytic activity and stability under conditions such as those encountered during a washing or cleaning process are therefore particularly desirable. Consequently, prior art formulations containing proteases, surfactants, and/or bleaching agents have the disadvantage that the proteases they contain do not have satisfactory proteolytic activity and/or are not sufficiently stable under standard washing and/or cleaning conditions, and the formulations therefore do not demonstrate optimal cleaning performance on protease-sensitive soils. Protease-sensitive soils are preferably selected from the group consisting of blood, egg (yolk), milk, and other protein-containing soils.

Das wichtigste Kriterium beim Reinigen von Textilien und/oder harten Oberflächen ist die Reinigungsleistung an verschiedensten Anschmutzungen. Auch wenn die Reinigungsleistung der heutzutage eingesetzten Wasch- und Reinigungsmittel generell hoch ist, stellt sich, auch aufgrund des generellen Trends vermehrt Niedrigtemperatur-Programme zu verwenden, allerdings das Problem, dass viele der üblichen Wasch- und Reinigungsmittel bei hartnäckigen Anschmutzungen eine unzureichende Wasch- bzw. Reinigungsleistung aufweisen. Eine solche unzureichende Wasch- bzw. Reinigungsleistung führen beim Verbraucher zu Unzufriedenheit und dazu, dass solche Anschmutzungen vom Verbraucher vorbehandelt werden, was wiederum den Wasser- und Energieverbrauch erhöht. Hartnäckige Verschmutzungen werden in gängigen Wasch- und Reinigungsmittel zudem üblicherweise mittels weiterer reinigungsaktiver Substanzen, wie z.B. Phosphonate und/oder Phosphate, adressiert. Aufgrund von Nachhaltigkeitsstreben und Bedenken hinsichtlich der Umweltverträglichkeit von Phosphaten und Phosphonaten in Wasch- und Reinigungsmittel werden zunehmend mehr Wasch- und Reinigungsmittel entwickelt, die wenig(er) bis keine phosphat- und/oder phosphonathaltigen Verbindungen enthalten. The most important criterion when cleaning textiles and/or hard surfaces is cleaning performance on a wide variety of soils. Even though the cleaning performance of the detergents and cleaning agents used today is generally high, the problem remains, also due to the general trend towards the increased use of low-temperature programs, that many conventional detergents and cleaning agents have insufficient washing or cleaning performance on stubborn soils. Such insufficient washing or cleaning performance leads to consumer dissatisfaction and leads to such soils being pre-treated by the consumer, which in turn increases water and energy consumption. Stubborn soils are also usually addressed in common detergents and cleaning agents using additional cleaning-active substances, such as phosphonates and/or phosphates. Due to sustainability efforts and concerns about the environmental compatibility of phosphates and phosphonates in detergents and cleaning agents, an increasing number of detergents and cleaning agents are being developed that contain little or no phosphate- and/or phosphonate-containing compounds.

Proteinhaltige Anschmutzungen, insbesondere Eianschmutzungen, sowie bleichbare Anschmutzungen, insbesondere Teeanschmutzungen, stellen hartnäckige Anschmutzungen dar, die oftmals nicht zufriedenstellend entfernt werden. Solche Anschmutzungen, insbesondere bleichbare Anschmutzungen, werden üblicherweise durch den Zusatz von Bleichmitteln in Wasch- und Reinigungsmitteln adressiert. Allerdings sind Enzyme in Gegenwart von Bleich- und/oder Oxidationsmitteln instabil und verlieren ihre Aktivität. Das gilt besonders für flüssige Wasch- und Reinigungsmittel. Deshalb ist die Wasch- bzw. Reinigungsleistung von herkömmlichen Wasch- und Reinigungsmitteln, die Enzyme und Bleichmittel in einer Zusammensetzung kombinieren, stark reduziert. Protein-containing soils, especially egg soils, and bleachable soils, especially tea soils, are stubborn stains that are often not satisfactorily removed. Such soils, especially bleachable soils, are typically addressed by adding bleaching agents to detergents and cleaning products. However, enzymes are unstable in the presence of bleaching and/or oxidizing agents and lose their activity. This is especially true for liquid detergents and cleaning products. Therefore, the washing and cleaning performance of conventional detergents and cleaning products that combine enzymes and bleaching agents in one composition is greatly reduced.

Es besteht daher Bedarf, die Wasch- bzw. Reinigungsleistung von bleichmittel- und enzymhaltigen, insbesondere proteasehaltigen, Wasch- und Reinigungsmitteln, insbesondere Maschinengeschirrspülmittel, zu verbessern, insbesondere hinsichtlich der Reinigungsleistung an proteasesensitiven Anschmutzungen. Besonderes Augenmerk der vorliegenden Erfindung liegt auf der Verbesserung der Stabilität von enzym- und bleichehaltigen Wasch- und Reinigungsmitteln, insbesondere der Stabilität von Enzymen in bleichehaltigen Wasch- und Reinigungsmitteln, bevorzugt der Stabilität von Proteasen in bleichehaltigen Wasch- und Reinigungsmitteln. Vorzugsweise wird die Verbesserung der Reinigungsleistung in einem Temperaturbereich von etwa 20°C bis etwa 75°C, bevorzugt von etwa 30°C bis etwa 60°C, weiter bevorzugt von etwa 40°C bis etwa 55°C. There is therefore a need to improve the washing and cleaning performance of bleach- and enzyme-containing, in particular protease-containing, detergents and cleaning agents, in particular dishwasher detergents, particularly with regard to the cleaning performance on protease-sensitive soils. Particular attention is paid to improving the stability of enzyme- and bleach-containing detergents and cleaning agents, in particular the stability of enzymes in bleach-containing detergents and cleaning agents, preferably the stability of proteases in bleach-containing detergents and cleaning agents. Preferably, the Improving cleaning performance in a temperature range from about 20°C to about 75°C, preferably from about 30°C to about 60°C, more preferably from about 40°C to about 55°C.

Überraschenderweise wurde jetzt festgestellt, dass eine Protease aus Bacillus gibsonii oder eine hierzu hinreichend ähnliche Protease (bezogen auf die Sequenzidentität), die bezogen auf die Nummerierung gemäß SEQ ID NO:1 (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, hinsichtlich ihrer Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, gegenüber einer Referenzprotease (Protease gemäß SEQ ID NO:1) verbessert ist, und daher besonders für den Einsatz in bleichmittelhaltigen Wasch- oder Reinigungsmitteln, insbesondere Maschinengeschirrspülmitteln, bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, geeignet ist. Surprisingly, it has now been found that a protease from Bacillus gibsonii or a sufficiently similar protease (in terms of sequence identity) which, based on the numbering according to SEQ ID NO:1, has (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution, which is selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, is improved with regard to its stability in the presence of bleaching agents, in particular oxidizing agents, compared to a reference protease (protease according to SEQ ID NO:1), and is therefore particularly suitable for use in bleach-containing washing or cleaning agents, in particular machine dishwashing agents, preferably bleach-containing machine dishwashing agents.

Gegenstand der Erfindung ist daher eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91%, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. The invention therefore relates to a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

Ein bevorzugter Gegenstand der Erfindung ist eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91%, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens zwei der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M1 17A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. A preferred subject of the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino acid substitutions selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

Ein weiter bevorzugter Gegenstand der Erfindung ist eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer, vorzugsweise zwei der Positionen, die den Positionen 211 und 212 entsprechen, mindestens eine, vorzugsweise zwei Aminosäuresubstitution(en), die aus der aus M211 N, M211 L, P212D und P212H, vorzugsweise M211 L und/oder P212D, bestehenden Gruppe ausgewählt ist/sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M1 17V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. A further preferred subject of the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one, preferably two of the positions corresponding to positions 211 and 212, at least one, preferably two amino acid substitution(s) selected from the group consisting of M211N, M211L, P212D and P212H, preferably M211L and/or P212D, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L existing group is selected.

Ein weiterer Gegenstand der Erfindung ist ein Verfahren zur Herstellung einer Protease, umfassend das Einbringen (i) mindestens einer Aminosäuresubstitution an mindestens einer der Positionen, die bezogen auf die Nummerierung gemäß SEQ ID NO:1 den Positionen 12, 43, 122, 127, 154, 156, 160, 21 1 , 212 und 222 entsprechen, ausgewählt aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M21 1 L, P212D, P212H und A222S bestehenden Gruppe, und (ii) mindestens einer Aminosäuresubstitution an mindestens einer der Positionen, die bezogen auf die Nummerierung gemäß SEQ ID NO:1 den Positionen 29, 58, 89, 117 und 216 entsprechen, ausgewählt aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe, in ein Ausgangsmolekül, das eine Aminosäuresequenz aufweist, die mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5%, 99%, 99,5% oder 100% Sequenzidentität mit der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge aufweist. The invention further relates to a process for the preparation of a protease, comprising introducing (i) at least one amino acid substitution at at least one of the positions which, based on the numbering according to SEQ ID NO:1, correspond to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one amino acid substitution at at least one of the positions which, based on the numbering according to SEQ ID NO:1, correspond to positions 29, 58, 89, 117 and 216, selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, into a starting molecule having an amino acid sequence which is at least 70% and increasingly preferably at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5% or 100% sequence identity with the amino acid sequence given in SEQ ID NO:1 over its entire length.

Eine Protease im Sinne der vorliegenden Patentanmeldung umfasst daher sowohl die Protease als solche als auch eine mit einem erfindungsgemäßen Verfahren hergestellte Protease. Alle Ausführungen zur Protease beziehen sich daher sowohl auf die Protease als solche wie auch auf die mittels entsprechender Verfahren hergestellten Proteasen, sowie auf die entsprechenden Verfahren, insbesondere Herstellungsverfahren der Protease. A protease within the meaning of the present patent application therefore encompasses both the protease itself and a protease produced by a process according to the invention. All statements regarding the protease therefore refer both to the protease itself and to the proteases produced by corresponding processes, as well as to the corresponding processes, in particular to the production processes of the protease.

Weitere Aspekte der Erfindung betreffen die für diese Proteasen codierenden Nukleinsäuren, erfindungsgemäße Proteasen oder Nukleinsäuren enthaltende nicht-menschliche Wirtszellen sowie erfindungsgemäße Proteasen umfassende Wasch- und Reinigungsmittel, insbesondere bleichmittelhaltige Wasch- und Reinigungsmittel, bevorzugt Maschinengeschirrspülmittel, besonders bevorzugt bleichmittelhaltige Maschinengeschirrspülmittel, Wasch- und Reinigungsverfahren, und Verwendungen der erfindungsgemäßen Proteasen in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltige Wasch- und Reinigungsmittel, bevorzugt Maschinengeschirrspülmittel, besonders bevorzugt bleichmittelhaltige Maschinengeschirrspülmittel, zur Entfernung von proteasesensitiven Anschmutzungen. Further aspects of the invention relate to the nucleic acids encoding these proteases, proteases according to the invention or nucleic acids containing non-human host cells and washing and cleaning agents comprising proteases according to the invention, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, washing and cleaning methods, and uses of the proteases according to the invention in washing or cleaning agents, in particular Bleach-containing washing and cleaning agents, preferably automatic dishwashing detergents, particularly preferably bleach-containing automatic dishwashing detergents, for removing protease-sensitive soiling.

Diese und weitere Aspekte, Merkmale und Vorteile der Erfindung werden für den Fachmann aus dem Studium der folgenden detaillierten Beschreibung und Ansprüche ersichtlich. Dabei kann jedes Merkmal aus einem Aspekt der Erfindung in jedem anderen Aspekt der Erfindung eingesetzt werden. Ferner ist es selbstverständlich, dass die hierin enthaltenen Beispiele die Erfindung beschreiben und veranschaulichen sollen, diese aber nicht einschränken und insbesondere die Erfindung nicht auf diese Beispiele beschränkt ist. These and other aspects, features, and advantages of the invention will become apparent to those skilled in the art from a study of the following detailed description and claims. It should be understood that any feature of one aspect of the invention may be employed in any other aspect of the invention. Furthermore, it is to be understood that the examples contained herein are intended to describe and illustrate the invention, but not to limit it, and in particular, the invention is not limited to these examples.

Alle Prozentangaben sind, sofern nicht anders angegeben, Gewichtsprozent (Gew.-%). Unless otherwise stated, all percentages are by weight (wt%).

Numerische Bereiche, die in dem Format "von x bis y" angegeben sind, schließen die genannten Werte ein. Wenn mehrere bevorzugte numerische Bereiche in diesem Format angegeben sind, ist es selbstverständlich, dass alle Bereiche, die durch die Kombination der verschiedenen Endpunkte entstehen, ebenfalls erfasst werden. Numerical ranges specified in the format "from x to y" include the specified values. If multiple preferred numerical ranges are specified in this format, it goes without saying that all ranges resulting from the combination of the different endpoints will also be included.

"Mindestens ein(e)", wie hierin verwendet, bedeutet ein(e) oder mehrere, d.h. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 oder mehr. "At least one" as used herein means one or more, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more.

Der Begriff "Wasch- und Reinigungsmittel" bzw. "Wasch- oder Reinigungsmittel", wie hierin verwendet, ist gleichbedeutend mit dem Begriff "Mittel" oder "Zusammensetzung" oder 'Wasch- und/oder Reinigungsmittelzusammensetzung" und bezeichnet eine Zusammensetzung zum Reinigen von Textilien und/oder harten Oberflächen, insbesondere Geschirr, wie in der Beschreibung erläutert. The term "washing and cleaning agent" or "washing or cleaning agent" as used herein is synonymous with the term "agent" or "composition" or "washing and/or cleaning agent composition" and refers to a composition for cleaning textiles and/or hard surfaces, in particular dishes, as explained in the description.

"Etwa", "ca." oder "ungefähr", wie hierin in Bezug auf einen Zahlenwert verwendet, beziehen sich auf den entsprechenden Zahlenwert ±10%, vorzugsweise ±5%. "Approximately," "approximately," or "approximately," as used herein with reference to a numerical value, refers to the corresponding numerical value ±10%, preferably ±5%.

"Im Wesentlichen frei von" bedeutet, dass die Zusammensetzung bzw. das Mittel weniger als 2 Gew.-%, vorzugsweise weniger als 1 Gew.-%, weiter bevorzugt weniger als 0,5 Gew.-% und besonders bevorzugt weniger als 0,1 Gew.-%, der entsprechenden Substanz, bezogen auf das Gesamtgewicht der Zusammensetzung/des Mittels, enthält. "Substantially free from" means that the composition or agent contains less than 2% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight and most preferably less than 0.1% by weight of the corresponding substance, based on the total weight of the composition/agent.

"Flüssig", wie hierin verwendet, schließt Flüssigkeiten und Gele sowie auch pastöse Zusammensetzungen ein. Es ist bevorzugt, dass die flüssigen Zusammensetzungen bei Raumtemperatur fließfähig und gießbar sind, es ist aber auch möglich, dass sie eine Fließgrenze aufweisen. "Liquid," as used herein, includes liquids and gels, as well as pasty compositions. It is preferred that the liquid compositions be flowable and pourable at room temperature, but it is also possible that they have a yield point.

Ein Stoff, z.B. eine Zusammensetzung oder ein Mittel ist gemäß Definition der Erfindung festförmig, wenn sie bei 25°C und 1 .013 mbar im festen Aggregatzustand vorliegt. A substance, e.g. a composition or an agent, is solid according to the definition of the invention if it is in the solid state at 25°C and 1,013 mbar.

Ein Stoff, z.B. eine Zusammensetzung oder ein Mittel ist gemäß Definition der Erfindung flüssig, wenn sie bei 25°C und 1.013 mbar im flüssigen Aggregatzustand vorliegt. Dabei umfasst flüssig auch gelförmig. "Variante", wie hierin verwendet, bezieht sich auf natürliche oder artifiziell erzeugte Variationen einer nativen Protease, die eine gegenüber der Referenzform abgewandelte Aminosäuresequenz aufweist. A substance, e.g., a composition or agent, is liquid according to the invention's definition if it exists in the liquid state at 25°C and 1,013 mbar. Liquid also includes gel. "Variant", as used herein, refers to natural or artificially produced variations of a native protease that have a modified amino acid sequence compared to the reference form.

Die vorliegende Erfindung basiert auf der überraschenden Erkenntnis der Erfinder, dass Aminosäuresubstitutionen an den hierin beschriebenen Positionen eine verbesserte Stabilität dieser veränderten Protease in Wasch- und Reinigungsmitteln, insbesondere bleichmittelhaltige Wasch- und Reinigungsmittel, bevorzugt Maschinengeschirrspülmittel, besonders bevorzugt bleichmittelhaltige Maschinengeschirrspülmittel, bewirkt. Die vorliegende Erfindung basiert insbesondere auf der überraschenden Erkenntnis der Erfinder, dass Aminosäuresubstitutionen an den hierin beschriebenen Positionen eine verbesserte Stabilität dieser veränderten Protease in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, bewirkt. The present invention is based on the surprising discovery of the inventors that amino acid substitutions at the positions described herein result in improved stability of this modified protease in detergents and cleaning agents, in particular detergents and cleaning agents containing bleach, preferably automatic dishwashing detergents, particularly preferably automatic dishwashing detergents containing bleach. The present invention is based in particular on the surprising discovery of the inventors that amino acid substitutions at the positions described herein result in improved stability of this modified protease in the presence of bleaching agents, in particular oxidizing agents.

In bevorzugten Ausführungsformen führen die erfindungsgemäßen Veränderungen (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, zu einer verbesserten Stabilität dieser veränderten Protease in Wasch- und Reinigungsmitteln, insbesondere bleichmittelhaltige Wasch- und Reinigungsmittel, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltige Maschinengeschirrspülmittel. In preferred embodiments, the changes according to the invention (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, leads to improved stability of this modified protease in washing and cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach.

In bevorzugten Ausführungsformen führen die erfindungsgemäßen Veränderungen (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, zu einer verbesserten Stabilität dieser veränderten Protease in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln. In preferred embodiments, the changes according to the invention (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, leads to improved stability of this modified protease in the presence of bleaching agents, in particular oxidizing agents.

Das ist insbesondere insoweit überraschend, als dass bisher keine Protease mit solchen Veränderungen für die Verwendung in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- oder Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, beschrieben wurden. Insbesondere wurden solche erfindungsgemäß veränderten Proteasen nicht im Zusammenhang mit einer verbesserten Stabilität, insbesondere verbesserten Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, beschrieben. This is particularly surprising insofar as no protease with such modifications has previously been described for use in washing or cleaning agents, in particular bleach-containing washing or cleaning agents, preferably automatic dishwashing agents, particularly preferably bleach-containing automatic dishwashing agents. In particular, such proteases modified according to the invention have not been described in connection with improved stability, in particular improved stability in the presence of bleaching agents, in particular oxidizing agents.

In bevorzugten Ausführungsformen weist die erfindungsgemäße Protease (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, auf, wobei die Kombination der mindestens einen Aminosäuresubstitution aus Gruppe (i) und der mindestens einen Aminosäuresubstitution aus Gruppe (ii) zu einer verbesserten Stabilität dieser veränderten Protease in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, führt. In preferred embodiments, the protease (i) according to the invention has at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the combination of the at least one amino acid substitution from group (i) and the at least one amino acid substitution from group (ii) leads to improved stability of this modified protease in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach.

In bevorzugten Ausführungsformen weist die erfindungsgemäße Protease (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, auf, wobei die Kombination der mindestens einen Aminosäuresubstitution aus Gruppe (i) und der mindestens einen Aminosäuresubstitution aus Gruppe (ii) zu einer verbesserten Stabilität dieser veränderten Protease in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, führt. In preferred embodiments, the protease according to the invention has (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the combination of the at least one amino acid substitution from group (i) and the at least one amino acid substitution from group (ii) leads to improved stability of this modified protease in the presence of bleaching agents, in particular oxidizing agents.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens zwei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least two of the positions corresponding to positions 29, 58, 89, 117 and 216, at least two amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens drei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens drei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least three of the positions corresponding to positions 29, 58, 89, 117 and 216, at least three amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens vier der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens vier Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least four of the positions corresponding to positions 29, 58, 89, 117 and 216, at least four amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an den Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, fünf Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at the positions corresponding to positions 29, 58, 89, 117 and 216, five amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens zwei der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino acid substitutions selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens zwei der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt sind, und (ii) an mindestens zwei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino acid substitutions selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least two of the positions corresponding to positions 29, 58, 89, 117 and 216, at least two amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens zwei der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt sind, und (ii) an mindestens drei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens drei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino acid substitutions selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at at least three of the positions corresponding to positions 29, 58, 89, 117 and 216 have at least three amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens zwei der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt sind, und (ii) an mindestens vier der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens vier Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino acid substitutions selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least four of the positions corresponding to positions 29, 58, 89, 117 and 216, at least four amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens zwei der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt sind, und (ii) an den Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, fünf Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino acid substitutions selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at the positions corresponding to positions 29, 58, 89, 117 and 216, five amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 211 und 212 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt ist/sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 211 und 212 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt ist/sind, und (ii) an mindestens zwei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least two of the positions corresponding to positions 29, 58, 89, 117 and 216, at least two amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 211 und 212 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt ist/sind, und (ii) an mindestens drei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens drei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least three of the positions corresponding to positions 29, 58, 89, 117 and 216, at least three amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 211 und 212 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt ist/sind, und (ii) an mindestens vier der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens vier Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least four of the positions corresponding to positions 29, 58, 89, 117 and 216, at least four amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 211 und 212 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt ist/sind, und (ii) an den Positionen, die den Positionen 29, 89, 117 und 216 entsprechen, fünf Aminosäuresubstitutionen, die aus der aus A29G, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to that shown in SEQ ID NO:1 specified amino acid sequence over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1 , (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at the positions corresponding to positions 29, 89, 117 and 216, five amino acid substitutions selected from the group consisting of A29G, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, zwei Aminosäuresubstitutionen, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, zwei Aminosäuresubstitutionen, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt sind, und (ii) an mindestens zwei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least two of the positions corresponding to positions 29, 58, 89, 117 and 216, at least two amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, zwei Aminosäuresubstitutionen, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt sind, und (ii) an mindestens drei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens drei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, where the protease, each with reference to the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least three amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L at least three of the positions corresponding to positions 29, 58, 89, 117 and 216.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, zwei Aminosäuresubstitutionen, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt sind, und (ii) an mindestens vier der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens vier Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least four of the positions corresponding to positions 29, 58, 89, 117 and 216, at least four amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, zwei Aminosäuresubstitutionen, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt sind, und (ii) an den Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, fünf Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, has (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at the positions corresponding to positions 29, 58, 89, 117 and 216, five amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, die Aminosäuresubstitutionen M211 L und P212D, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, die Aminosäuresubstitutionen M211 L und P212D, und (ii) an mindestens zwei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least two of the positions corresponding to positions 29, 58, 89, 117 and 216, at least two amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, die Aminosäuresubstitutionen M211 L und P212D, und (ii) an mindestens drei der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens drei Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least three of the positions corresponding to positions 29, 58, 89, 117 and 216, at least three amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, die Aminosäuresubstitutionen M211 L und P212D, und (ii) an mindestens vier der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens vier Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least four of the positions corresponding to positions 29, 58, 89, 117 and 216, at least four amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, die Aminosäuresubstitutionen M211 L und P212D, und (ii) an den Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, fünf Aminosäuresubstitutionen, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt sind, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO: 1, has (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at the positions corresponding to positions 29, 58, 89, 117 and 216, five amino acid substitutions selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H und Q12L-M122L-A222S bestehenden Gruppe ausgewählt ist, und (ii) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus A29G, A29G-D58P, A29G-Y89A, A29G-M117A, A29G-M117F, A29G-M1171, A29G- M117L, A29G-M117V, A29G-M216A, A29G-M216F, A29G-M216L, A29G-D58P-Y89A, A29G-D58P- M117A, A29G-D58P-M117F, A29G-D58P-M1171, A29G-D58P-M117L, A29G-D58P-M117V, A29G- D58P-M216A, A29G-D58P-M216F, A29G-D58P-M216L, A29G-Y89A-M117A, A29G-Y89A-M117F, A29G-Y89A-M1171, A29G-Y89A-M117L, A29G-Y89A-M117V, A29G-Y89A-M216A, A29G-Y89A- M216F, A29G-Y89A-M216L, A29G-M117A-M216A, A29G-M117A-M216F, A29G-M117A-M216L, A29G-D58P-Y89A-M117A, A29G-D58P-Y89A-M117F, A29G-D58P-Y89A-M1171, A29G-D58P-Y89A- M117L, A29G-D58P-Y89A-M117V, A29G-D58P-Y89A-M216A, A29G-D58P-Y89A-M216F, A29G- D58P-Y89A-M216L, A29G-Y89A-M117A-M216A, A29G-Y89A-M117A-M216F, A29G-Y89A-M117A- M216L, A29G-Y89A-M117F-M216A, A29G-Y89A-M117F-M216F, A29G-Y89A-M117F-M216L, A29G- Y89A-M117I-M216A, A29G-Y89A-M117I-M216F, A29G-Y89A-M117I-M216L, A29G-Y89A-M117L- M216A, A29G-Y89A-M117L-M216F, A29G-Y89A-M117L-M216L, A29G-Y89A-M117V-M216A, A29G- Y89A-M117V-M216F, A29G-Y89A-M117V-M216L, D58P, D58P-Y89A, D58P-M117A, D58P-M117F, D58P-M1171, D58P-M117L, D58P-M117V, D58P-M216A, D58P-M216F, D58P-M216L, D58P-Y89A- M117A, D58P-Y89A-M117F, D58P-Y89A-M1171, D58P-Y89A-M117L, D58P-Y89A-M117V, D58P- Y89A-M216A, D58P-Y89A-M216F, D58P-Y89A-M216L, D58P-M117A-M216A, D58P-M117A-M216F, D58P-M117A-M216L, D58P-M117F-M216A, D58P-M117F-M216F, D58P-M117F-M216L, D58P- M117I-M216A, D58P-M117I-M216F, D58P-M117I-M216L, D58P-M117L-M216A, D58P-M117L- M216F, D58P-M117L-M216L, D58P-M117V-M216A, D58P-M117V-M216F, D58P-M117V-M216L, Y89A, Y89A-M117A, Y89A-M117F, Y89A-M1171, Y89A-M117L, Y89A-M117V, Y89A-M216A, Y89A- M216F, Y89A-M216L, Y89A-M117A-M216A, Y89A-M117A-M216F, Y89A-M117A-M216L, Y89A- M117F-M216A, Y89A-M117F-M216F, Y89A-M117F-M216L, Y89A-M117I-M216A, Y89A-M117I- M216F, Y89A-M117I-M216L, Y89A-M117L-M216A, Y89A-M117L-M216F, Y89A-M117L-M216L, Y89A-M117V-M216A, Y89A-M117V-M216F, Y89A-M117V-M216L, M117A, M117F, M117I, M117L, M117V, M117A-M216A, M117A-M216F, M117A-M216L, M117F-M216A, M117F-M216F, M117F- M216L, M117I-M216A, M117I-M216F, M117I-M216L, M117L-M216A, M117L-M216F, M117L-M216L, M117V-M216A, M117V-M216F, M117V-M216L, M216A, M216F, M216L bestehenden Gruppe ausgewählt ist, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H and Q12L-M122L-A222S, and (ii) an amino acid substitution or amino acid substitution combination selected from the group consisting of A29G, A29G-D58P, A29G-Y89A, A29G-M117A, A29G-M117F, A29G-M1171, A29G- M117L, A29G-M117V, A29G-M216A, A29G-M216F, A29G-M216L, A29G-D58P-Y89A, A29G-D58P-M117A, A29G-D58P-M117F, A29G-D58P-M1171, A29G-D58P-M117L, A29G-D58P-M117V, A29G-D58P-M216A, A29G-D58P-M216F, A29G-D58P-M216L, A29G-Y89A-M117A, A29G-Y89A-M117F, A29G-Y89A-M1171, A29G-Y89A-M117L, A29G-Y89A-M117V, A29G-Y89A-M216A, A29G-Y89A-M216F, A29G-Y89A-M216L, A29G-M117A-M216A, A29G-M117A-M216F, A29G-M117A-M216L, A29G-D58P-Y89A-M117A, A29G-D58P-Y89A-M117F, A29G-D58P-Y89A-M1171, A29G-D58P-Y89A-M117L, A29G-D58P-Y89A-M117V, A29G-D58P-Y89A-M216A, A29G-D58P-Y89A-M216F, A29G-D58P-Y89A-M216L, A29G-Y89A-M117A-M216A, A29G-Y89A-M117A-M216F, A29G-Y89A-M117A-M216L, A29G-Y89A-M117F-M216A, A29G-Y89A-M117F-M216F, A29G-Y89A-M117F-M216L, A29G-Y89A-M117I-M216A, A29G-Y89A-M117I-M216F, A29G-Y89A-M117I-M216L, A29G-Y89A-M117L- M216A, A29G-Y89A-M117L-M216F, A29G-Y89A-M117L-M216L, A29G-Y89A-M117V-M216A, A29G- Y89A-M117V-M216F, A29G-Y89A-M117V-M216L, D58P, D58P-Y89A, D58P-M117A, D58P-M117F, D58P-M1171, D58P-M117L, D58P-M117V, D58P-M216A, D58P-M216F, D58P-M216L, D58P-Y89A-M117A, D58P-Y89A-M117F, D58P-Y89A-M1171, D58P-Y89A-M117L, D58P-Y89A-M117V, D58P-Y89A-M216A, D58P-Y89A-M216F, D58P-Y89A-M216L, D58P-M117A-M216A, D58P-M117A-M216F, D58P-M117A-M216L, D58P-M117F-M216A, D58P-M117F-M216F, D58P-M117F-M216L, D58P- M117I-M216A, D58P-M117I-M216F, D58P-M117I-M216L, D58P-M117L-M216A, D58P-M117L-M216F, D58P-M117L-M216L, D58P-M117V-M216A, D58P-M117V-M216F, D58P-M117V-M216L, Y89A, Y89A-M117A, Y89A-M117F, Y89A-M1171, Y89A-M117L, Y89A-M117V, Y89A-M216A, Y89A-M216F, Y89A-M216L, Y89A-M117A-M216A, Y89A-M117A-M216F, Y89A-M117A-M216L, Y89A-M117F-M216A, Y89A-M117F-M216F, Y89A-M117F-M216L, Y89A-M117I-M216A, Y89A-M117I-M216F, Y89A-M117I-M216L, Y89A-M117L-M216A, Y89A-M117L-M216F, Y89A-M117L-M216L, Y89A-M117V-M216A, Y89A-M117V-M216F, Y89A-M117V-M216L, M117A, M117F, M117I, M117L, M117V, M117A-M216A, M117A-M216F, M117A-M216L, M117F-M216A, M117F-M216F, M117F- M216L, M117I-M216A, M117I-M216F, M117I-M216L, M117L-M216A, M117L-M216F, M117L-M216L, M117V-M216A, M117V-M216F, M117V-M216L, M216A, M216F, M216L.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H und Q12L-M122L-A222S bestehenden Gruppe ausgewählt ist, und (ii) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus M117A, M117A-Y89L, M117V, M117V-A29G, M117F, M117I, M117L, M216F, D58P- M216A, M216L bestehenden Gruppe ausgewählt ist, aufweist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H and Q12L-M122L-A222S, and (ii) an amino acid substitution or amino acid substitution combination selected from the group consisting of M117A, M117A-Y89L, M117V, M117V-A29G, M117F, M117I, M117L, M216F, D58P- M216A, M216L existing group is selected.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , eine Aminosäuresubstitutionskombination aufweist, die aus der aus I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M117I, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P- M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P-M216L, I43V-A29G-Y89A-M117A, I43V-A29G- Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G-Y89A-M117L, I43V-A29G-Y89A-M117V, I43V- A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V-A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A-M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G- D58P-Y89A-M117F, I43V-A29G-D58P-Y89A-M1171, I43V-A29G-D58P-Y89A-M117L, I43V-A29G- D58P-Y89A-M117V, I43V-A29G-D58P-Y89A-M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G- D58P-Y89A-M216L, I43V-A29G-Y89A-M117A-M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G- Y89A-M117A-M216L, I43V-A29G-Y89A-M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V- A29G-Y89A-M117F-M216L, I43V-A29G-Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V- A29G-Y89A-M117I-M216L, I43V-A29G-Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V- A29G-Y89A-M117L-M216L, I43V-A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P- M117F, I43V-D58P-M1171, I43V-D58P-M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P- M216F, I43V-D58P-M216L, I43V-D58P-Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A- M117I, I43V-D58P-Y89A-M117L, I43V-D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P- Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V- D58P-M117A-M216L, I43V-D58P-M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F- M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P- M117L-M216A, I43V-D58P-M117L-M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V-D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A- M117F, I43V-Y89A-M1171, I43V-Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A- M216F, I43V-Y89A-M216L, I43V-Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A- M117A-M216L, I43V-Y89A-M117F-M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V-Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L- M216A, I43V-Y89A-M117L-M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V- Y89A-M117V-M216F, I43V-Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V- M117L, I43V-M117V, I43V-M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F- M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V- M117I-M216L, I43V-M117L-M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V-M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S- T156A-A29G, M122L-N154S-T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S- T156A-A29G-M117A, M122L-N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M1171, M122L-N154S-T156A-A29G-M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A- A29G-M216A, M122L-N154S-T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L- N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A- A29G-D58P-M117F, M122L-N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P- M117L, 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N-P212D-M117V-M216A, M211 N-P212D-M117V-M216F, M211 N-P212D-M117V-M216L, M211 N-P212D-M216A, M211 N- P212D-M216F, M211 N-P212D-M216L, M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L- P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D- A29G-M117I, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G- M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P- Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G- D58P-M1171, M21 1 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D- A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L- P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M1171, M211 L-P212D-A29G-Y89A-M117L, M21 1 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A- M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D- A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M21 1 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D- A29G-D58P-Y89A-M117I , M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P- Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L- P212D-A29G-Y89A-M117A-M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L-P212D- A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A- M1 17F-M216L, M21 1 L-P212D-A29G-Y89A-M117I-M216A, M21 1 L-P212D-A29G-Y89A-M1 17I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L- P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G- Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M21 1 L-P212D-A29G-Y89A- M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M21 1 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M1 17L, M211 L- P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D- D58P-M216L, M211 L-P212D-D58P-Y89A-M1 17A, M211 L-P212D-D58P-Y89A-M117F, M211 L- P212D-D58P-Y89A-M1 171, M21 1 L-P212D-D58P-Y89A-M117L, M21 1 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A- M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M1 17A-M216F, M211 L-P212D- D58P-M1 17A-M216L, M211 L-P212D-D58P-M117F-M216A, M21 1 L-P212D-D58P-M1 17F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P-M1 17I-M216A, M211 L-P212D-D58P- M1 17I-M216F, M211 L-P212D-D58P-M1 17I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L- P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D-D58P-M117V- M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D- Y89A, M211 L-P212D-Y89A-M1 17A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M117I, M21 1 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L- P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L- P212D-Y89A-M117A-M216F, M21 1 L-P212D-Y89A-M1 17A-M216L, M211 L-P212D-Y89A-M117F- M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D- Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A- M1 17L-M216L, M211 L-P212D-Y89A-M117V-M216A, M21 1 L-P212D-Y89A-M117V-M216F, M211 L- P212D-Y89A-M117V-M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M21 1 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A- M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L- P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D- M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V- M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L, G160S-A29G, G160S- A29G-D58P, G160S-A29G-Y89A, G160S-A29G-M117A, G160S-A29G-M117F, G160S-A29G-M1171, G160S-A29G-M117L, G160S-A29G-M117V, G160S-A29G-M216A, G160S-A29G-M216F, G160S- A29G-M216L, G160S-A29G-D58P-Y89A, G160S-A29G-D58P-M117A, G160S-A29G-D58P-M117F, G160S-A29G-D58P-M1171, G160S-A29G-D58P-M117L, G160S-A29G-D58P-M117V, G160S-A29G- D58P-M216A, G160S-A29G-D58P-M216F, G160S-A29G-D58P-M216L, G160S-A29G-Y89A-M117A, G160S-A29G-Y89A-M117F, G160S-A29G-Y89A-M1171, G160S-A29G-Y89A-M117L, G160S-A29G- Y89A-M117V, G160S-A29G-Y89A-M216A, G160S-A29G-Y89A-M216F, G160S-A29G-Y89A-M216L, G160S-A29G-M117A-M216A, G160S-A29G-M117A-M216F, G160S-A29G-M117A-M216L, G160S- A29G-D58P-Y89A-M117A, G160S-A29G-D58P-Y89A-M117F, G160S-A29G-D58P-Y89A-M117I, G160S-A29G-D58P-Y89A-M117L, G160S-A29G-D58P-Y89A-M117V, G160S-A29G-D58P-Y89A- M216A, G160S-A29G-D58P-Y89A-M216F, G160S-A29G-D58P-Y89A-M216L, G160S-A29G-Y89A- M117A-M216A, G160S-A29G-Y89A-M117A-M216F, G160S-A29G-Y89A-M117A-M216L, G160S- A29G-Y89A-M117F-M216A, G160S-A29G-Y89A-M117F-M216F, G160S-A29G-Y89A-M117F-M216L, G160S-A29G-Y89A-M117I-M216A, G160S-A29G-Y89A-M117I-M216F, G160S-A29G-Y89A-M1171- M216L, G160S-A29G-Y89A-M117L-M216A, G160S-A29G-Y89A-M117L-M216F, G160S-A29G-Y89A- M117L-M216L, G160S-A29G-Y89A-M117V-M216A, G160S-A29G-Y89A-M117V-M216F, G160S- A29G-Y89A-M117V-M216L, G160S-D58P, G160S-D58P-Y89A, G160S-D58P-M117A, G160S-D58P- M117F, G160S-D58P-M1171, G160S-D58P-M117L, G160S-D58P-M117V, G160S-D58P-M216A, G160S-D58P-M216F, G160S-D58P-M216L, G160S-D58P-Y89A-M117A, G160S-D58P-Y89A-M117F, G160S-D58P-Y89A-M1171, G160S-D58P-Y89A-M117L, G160S-D58P-Y89A-M117V, G160S-D58P- Y89A-M216A, G160S-D58P-Y89A-M216F, G160S-D58P-Y89A-M216L, G160S-D58P-M117A-M216A, G160S-D58P-M117A-M216F, G160S-D58P-M117A-M216L, G160S-D58P-M117F-M216A, G160S- D58P-M117F-M216F, G160S-D58P-M117F-M216L, G160S-D58P-M117I-M216A, G160S-D58P- M117I-M216F, G160S-D58P-M117I-M216L, G160S-D58P-M117L-M216A, G160S-D58P-M117L- M216F, G160S-D58P-M117L-M216L, G160S-D58P-M117V-M216A, G160S-D58P-M117V-M216F, G160S-D58P-M117V-M216L, G160S-Y89A, G160S-Y89A-M117A, G160S-Y89A-M117F, G160S- Y89A-M117I, G160S-Y89A-M117L, G160S-Y89A-M117V, G160S-Y89A-M216A, G160S-Y89A- M216F, G160S-Y89A-M216L, G160S-Y89A-M117A-M216A, G160S-Y89A-M117A-M216F, G160S- Y89A-M117A-M216L, G160S-Y89A-M117F-M216A, G160S-Y89A-M117F-M216F, G160S-Y89A- M117F-M216L, G160S-Y89A-M117I-M216A, G160S-Y89A-M117I-M216F, G160S-Y89A-M1171- M216L, G160S-Y89A-M117L-M216A, G160S-Y89A-M117L-M216F, G160S-Y89A-M117L-M216L, G160S-Y89A-M117V-M216A, G160S-Y89A-M117V-M216F, G160S-Y89A-M117V-M216L, G160S- M117A, G160S-M117F, G160S-M117I, G160S-M117L, G160S-M117V, G160S-M117A-M216A, G160S-M117A-M216F, G160S-M117A-M216L, G160S-M117F-M216A, G160S-M117F-M216F, G160S-M117F-M216L, G160S-M117I-M216A, G160S-M117I-M216F, G160S-M117I-M216L, G160S- M117L-M216A, G160S-M117L-M216F, G160S-M117L-M216L, G160S-M117V-M216A, G160S- M117V-M216F, G160S-M117V-M216L, G160S-M216A, G160S-M216F, G160S-M216L, D127P- M211 L-P212D-A29G, D127P-M211 L-P212D-A29G-D58P, D127P-M211 L-P212D-A29G-Y89A, D127P-M211 L-P212D-A29G-M117A, D127P-M211 L-P212D-A29G-M117F, D127P-M211 L-P212D- A29G-M117I, D127P-M211 L-P212D-A29G-M117L, D127P-M211 L-P212D-A29G-M117V, D127P- M211 L-P212D-A29G-M216A, D127P-M211 L-P212D-A29G-M216F, D127P-M211 L-P212D-A29G- M216L, D127P-M211 L-P212D-A29G-D58P-Y89A, D127P-M211 L-P212D-A29G-D58P-M117A, D127P-M211 L-P212D-A29G-D58P-M117F, D127P-M211 L-P212D-A29G-D58P-M1171, D127P- M211 L-P212D-A29G-D58P-M117L, D127P-M211 L-P212D-A29G-D58P-M117V, D127P-M211 L- P212D-A29G-D58P-M216A, D127P-M211 L-P212D-A29G-D58P-M216F, D127P-M211 L-P212D- A29G-D58P-M216L, D127P-M211 L-P212D-A29G-Y89A-M117A, D127P-M211 L-P212D-A29G-Y89A- M117F, D127P-M211 L-P212D-A29G-Y89A-M1171, D127P-M211 L-P212D-A29G-Y89A-M117L, D127P-M211 L-P212D-A29G-Y89A-M117V, D127P-M211 L-P212D-A29G-Y89A-M216A, D127P- M211 L-P212D-A29G-Y89A-M216F, D127P-M211 L-P212D-A29G-Y89A-M216L, D127P-M211 L- P212D-A29G-M117A-M216A, D127P-M211 L-P212D-A29G-M117A-M216F, D127P-M211 L-P212D- A29G-M117A-M216L, D127P-M211 L-P212D-A29G-D58P-Y89A-M117A, D127P-M211 L-P212D- A29G-D58P-Y89A-M117F, D127P-M211 L-P212D-A29G-D58P-Y89A-M1171, D127P-M211 L-P212D- A29G-D58P-Y89A-M117L, D127P-M211 L-P212D-A29G-D58P-Y89A-M117V, D127P-M211 L-P212D- A29G-D58P-Y89A-M216A, D127P-M211 L-P212D-A29G-D58P-Y89A-M216F, D127P-M211 L-P212D- A29G-D58P-Y89A-M216L, D127P-M211 L-P212D-A29G-Y89A-M117A-M216A, D127P-M211 L- P212D-A29G-Y89A-M117A-M216F, D127P-M211 L-P212D-A29G-Y89A-M117A-M216L, D127P- M211 L-P212D-A29G-Y89A-M117F-M216A, D127P-M211 L-P212D-A29G-Y89A-M117F-M216F, D127P-M211 L-P212D-A29G-Y89A-M117F-M216L, D127P-M211 L-P212D-A29G-Y89A-M117I-M216A, D127P-M211 L-P212D-A29— Y89A-M117I-M216F, D127P-M211 L-P212D-A29G-Y89A-M117I-M216L, D127P-M211 L-P212D-A29G-Y89A-M117L-M216A, D127P-M211 L-P212D-A29G-Y89A-M117L- M216F, D127P-M211 L-P212D-A29G-Y89A-M117L-M216L, D127P-M211 L-P212D-A29G-Y89A- M117V-M216A, D127P-M211 L-P212D-A29G-Y89A-M117V-M216F, D127P-M211 L-P212D-A29G- Y89A-M117V-M216L, D127P-M211 L-P212D-D58P, D127P-M211 L-P212D-D58P-Y89A, D127P- M211 L-P212D-D58P-M117A, D127P-M211 L-P212D-D58P-M117F, D127P-M211 L-P212D-D58P- M117I, D127P-M211 L-P212D-D58P-M117L, D127P-M211 L-P212D-D58P-M117V, D127P-M211 L- P212D-D58P-M216A, D127P-M211 L-P212D-D58P-M216F, D127P-M211 L-P212D-D58P-M216L, D127P-M211 L-P212D-D58P-Y89A-M117A, D127P-M211 L-P212D-D58P-Y89A-M117F, D127P-In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M117I, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P-M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P-M216L, I43V-A29G-Y89A-M117A, I43V-A29G-Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G-Y89A-M117L, I43V-A29G-Y89A-M117V, I43V-A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V-A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A-M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G-D58P-Y89A-M117F, I43V-A29G-D58P-Y89A-M1171, I43V-A29G-D58P-Y89A-M117L, I43V-A29G-D58P-Y89A-M117V, I43V-A29G-D58P-Y89A-M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G- D58P-Y89A-M216L, I43V-A29G-Y89A-M117A-M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G- Y89A-M117A-M216L, I43V-A29G-Y89A-M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V-A29G-Y89A-M117F-M216L, I43V-A29G-Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V- A29G-Y89A-M117I-M216L, I43V-A29G-Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V- A29G-Y89A-M117L-M216L, I43V-A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P-M117F, I43V-D58P-M1171, I43V-D58P-M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P-M216F, I43V-D58P-M216L, I43V-D58P-Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A-M117I, I43V-D58P-Y89A-M117L, I43V-D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P- Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V-D58P-M117A-M216L, I43V-D58P-M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F-M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P- M117L-M216A, I43V-D58P-M117L-M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V-D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A-M117F, I43V-Y89A-M1171, I43V-Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A-M216F, I43V-Y89A-M216L, I43V-Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A-M117A-M216L, I43V-Y89A-M117F-M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V-Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L-M216A, I43V-Y89A-M117L-M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V-Y89A-M117V-M216F, I43V-Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V-M117L, I43V-M117V, I43V-M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F- M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V-M117I-M216L, I43V-M117L-M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V-M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S-T156A-A29G, M122L-N154S-T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S-T156A-A29G-M117A, M122L-N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M1171, M122L-N154S-T156A-A29G-M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A-A29G-M216A, M122L-N154S-T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L-N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A- A29G-D58P-M117F, M122L-N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P-M117L, M122L-N154S-T156A-A29G-D58P-M117V, M122L-N154S-T156A-A29G-D58P-M216A, M122L-N154S-T156A-A29G-D58P-M216F, M122L-N154S-T156A-A29G-D58P-M216L, M122L- N154S-T156A-A29G-Y89A-M117A, M122L-N154S-T156A-A29G-Y89A-M117F, M122L-N154S- T156A-A29G-Y89A-M117I, M122L-N154S-T156A-A29G-Y89A-M117L, M122L-N154S-T156A-A29G-Y89A-M117V, M122L-N154S-T156A-A29G-Y89A-M216A, M122L-N154S-T156A-A29G-Y89A-M216F, M122L-N154S-T156A-A29G-Y89A-M216L, M122L-N154S-T156A-A29G-M117A-M216A, M122L- N154S-T156A-A29G-M117A-M216F, M122L-N154S-T156A-A29G-M117A-M216L, M122L-N154S-T156A-A29G-D58P-Y89A-M117A, M122L-N154S-T156A-A29G-D58P-Y89A-M117F, M122L-N154S-T156A-A29G-D58P-Y89A-M1171, M122L-N154S-T156A-A29G-D58P-Y89A-M117L, M122L-N154S-T156A-A29G-D58P-Y89A-M117V, M122L-N154S-T156A-A29G-D58P-Y89A-M216A, M122L-N154S-T156A-A29G-D58P-Y89A-M216F, M122L-N154S-T156A-A29G-D58P-Y89A-M216L, M122L-N154S- T156A-A29G-Y89A-M117A-M216A, M122L-N154S-T156A-A29G-Y89A-M117A-M216F, M122L- N154S-T156A-A29G-Y89A-M117A-M216L, M122L-N154S-T156A-A29G-Y89A-M117F-M216A, M122L-N154S-T156A-A29G-Y89A-M117F-M216F, M122L-N154S-T156A-A29G-Y89A-M117F- M216L, M122L-N154S-T156A-A29G-Y89A-M117I-M216A, M122L-N154S-T156A-A29G-Y89A-M117I-M216F, M122L-N154S-T156A-A29G-Y89A-M117I-M216L, M122L-N154S-T156A-A29G-Y89A-M117L- M216A, M122L-N154S-T156A-A29G-Y89A-M117L-M216F, M122L-N154S-T156A-A29G-Y89A- M117L-M216L, M122L-N154S-T156A-A29G-Y89A-M117V-M216A, M122L-N154S-T156A-A29G-Y89A-M117V-M216F, M122L-N154S-T156A-A29G-Y89A-M117V-M216L, M122L-N154S-T156A- D58P, M122L-N154S-T156A-D58P-Y89A, M122L-N154S-T156A-D58P-M117A, M122L-N154S- T156A-D58P-M117F, M122L-N154S-T156A-D58P-M1171, M122L-N154S-T156A-D58P-M117L, M122L-N154S-T156A-D58P-M117V, M122L-N154S-T156A-D58P-M216A, M122L-N154S-T156A-D58P-M216F, M122L-N154S-T156A-D58P-M216L, M122L-N154S-T156A-D58P-Y89A-M117A, M122L-N154S-T156A-D58P-Y89A-M117F, M122L-N154S-T156A-D58P-Y89A-M117I, M122L-N154S-T156A-D58P-Y89A-M117L, M122L-N154S-T156A-D58P-Y89A-M117V, M122L-N154S-T156A-D58P-Y89A-M216A, M122L-N154S-T156A-D58P-Y89A-M216F, M122L-N154S-T156A-D58P-Y89A-M216L, M122L-N154S-T156A-D58P-M117A-M216A, M122L-N154S-T156A-D58P-M117A-M216F, M122L-N154S-T156A-D58P-M117A-M216L, M122L-N154S-T156A-D58P-M117F-M216A, M122L-N154S-T156A-D58P-M117F-M216F, M122L-N154S-T156A-D58P-M117F-M216L, M122L-N154S-T156A-D58P-M117I-M216A, M122L-N154S-T156A-D58P-M117I-M216F, M122L-N154S-T156A-D58P-M117I-M216L, M122L-N154S-T156A-D58P-M117L-M216A, M122L-N154S-T156A-D58P-M117L- M216F, M122L-N154S-T156A-D58P-M117L-M216L, M122L-N154S-T156A-D58P-M117V-M216A, M122L-N154S-T156A-D58P-M117V-M216F, M122L-N154S-T156A-D58P-M117V-M216L, M122L-N154S-T156A-Y89A, M122L-N154S-T156A-Y89A-M117A, M122L-N154S-T156A-Y89A-M117F, M122L-N154S-T156A-Y89A-M117I, M122L-N154S-T156A-Y89A-M117L, M122L-N154S-T156A-Y89A-M117V, M122L-N154S-T156A-Y89A-M216A, M122L-N154S-T156A-Y89A-M216F, M122L- N154S-T156A-Y89A-M216L, M122L-N154S-T156A-Y89A-M117A-M216A, M122L-N154S-T156A- Y89A-M117A-M216F, M122L-N154S-T156A-Y89A-M117A-M216L, M122L-N154S-T156A-Y89A- M117F-M216A, M122L-N154S-T156A-Y89A-M117F-M216F, M122L-N154S-T156A-Y89A-M117F- M216L, M122L-N154S-T156A-Y89A-M117I-M216A, M122L-N154S-T156A-Y89A-M117I-M216F, M122L-N154S-T156A-Y89A-M117I-M216L, M122L-N154S-T156A-Y89A-M117L-M216A, M122L-N154S-T156A-Y89A-M117L-M216F, M122L-N154S-T156A-Y89A-M117L-M216L, M122L-N154S- T156A-Y89A-M117V-M216A, M122L-N154S-T156A-Y89A-M117V-M216F, M122L-N154S-T156A- Y89A-M117V-M216L, M122L-N154S-T156A-M117A, M122L-N154S-T156A-M117F, M122L-N154S-T156A-M117I, M122L-N154S-T156A-M117L, M122L-N154S-T156A-M117V, M122L-N154S-T156A- M117A-M216A, M122L-N154S-T156A-M117A-M216F, M122L-N154S-T156A-M117A-M216L, M122L-N154S-T156A-M117F-M216A, M122L-N154S-T156A-M117F-M216F, M122L-N154S-T156A-M117F-M216L, M122L-N154S-T156A-M117I-M216A, M122L-N154S-T156A-M117I-M216F, M122L-N154S- T156A-M117I-M216L, M122L-N154S-T156A-M117L-M216A, M122L-N154S-T156A-M117L-M216F, M122L-N154S-T156A-M117L-M216L, M122L-N154S-T156A-M117V-M216A, M122L-N154S-T156A- M117V-M216F, M122L-N154S-T156A-M117V-M216L, M122L-N154S-T156A-M216A, M122L-N154S-T156A-M216F, M122L-N154S-T156A-M216L, M211 N-P212D-A29G, M211 N-P212D-A29G-D58P, M211 N-P212D-A29G-Y89A, M211 N-P212D-A29G-M117A, M211 N-P212D-A29G-M117F, M211 N-P212D-A29G-M1171, M211 N-P212D-A29G-M117L, M211 N-P212D-A29G-M117V, M211 N-P212D-A29G-M216A, M211 N-P212D-A29G-M216F, M211 N-P212D-A29G-M216L, M211 N-P212D-A29G- D58P-Y89A, M211 N-P212D-A29G-D58P-M117A, M211 N-P212D-A29G-D58P-M117F, M211 N- P212D-A29G-D58P-M1171, M211 N-P212D-A29G-D58P-M117L, M211 N-P212D-A29G-D58P-M117V, M211 N-P212D-A29G-D58P-M216A, M211 N-P212D-A29G-D58P-M216F, M211 N-P212D-A29G- D58P-M216L, M211 N-P212D-A29G-Y89A-M117A, M211 N-P212D-A29G-Y89A-M117F, M211 N- P212D-A29G-Y89A-M117I, M211 N-P212D-A29G-Y89A-M117L, M211 N-P212D-A29G-Y89A-M117V, M211 N-P212D-A29G-Y89A-M216A, M211 N-P212D-A29G-Y89A-M216F, M211 N-P212D-A29G-Y89A- M216L, M211 N-P212D-A29G-M117A-M216A, M211 N-P212D-A29G-M117A-M216F, M211 N-P212D- A29G-M117A-M216L, M211 N-P212D-A29G-D58P-Y89A-M117A, M211 N-P212D-A29G-D58P-Y89A-M117F, M211 N-P212D-A29G-D58P-Y89A-M117I, M211 N-P212D-A29G-D58P-Y89A-M117L, M211 N- P212D-A29G-D58P-Y89A-M117V, M211 N-P212D-A29G-D58P-Y89A-M216A, M211 N-P212D-A29G- D58P-Y89A-M216F, M211 N-P212D-A29G-D58P-Y89A-M216L, M211 N-P212D-A29G-Y89A-M117A- M216A, M211 N-P212D-A29G-Y89A-M117A-M216F, M211 N-P212D-A29G-Y89A-M117A-M216L, M211 N-P212D-A29G-Y89A-M117F-M216A, M211 N-P212D-A29G-Y89A-M117F-M216F, M211 N-P212D-A29G-Y89A-M117F-M216L, M211 N-P212D-A29G-Y89A-M117I-M216A, M211 N-P212D-A29— Y89A-M117I-M216F, M211 N-P212D-A29G-Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L- M216A, M211 N-P212D-A29G-Y89A-M117L-M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 N-P212D-A29G-Y89A-M117V-M216A, M211 N-P212D-A29G-Y89A-M117V-M216F, M211 N- P212D-A29— Y89A-M117V-M216L, M211 N-P212D-D58P, M211 N-P212D-D58P-Y89A, M211 N- P212D-D58P-M117A, M211 M211 N-P212D-D58P-M117F N-P212D-D58P- M216F, M211 N-P212D-D58P-M216L, M211N-P212D-D58P-Y89A-M117A, M211 N-P212D-D58P- Y89A-M117F, M211 N-P212D-D58P-Y89A-M117I, M211 N-P212D-D58P-Y89A-M117L, M211 N-P212D-D58P-Y89A-M117V, M211 N-P212D-D58P-Y89A-M216A, M211 N-P212D-D58P-Y89A-M216F, M211 M211 N-P212D-D58P-M117A-M216L, M211 N-P212D-D58P-M117A-M216L, M211 M211 M211 N-P212D-D58P-M117L-M216F, M211 M211 N-P212D-D58P-M117V-M216L, M211 N-P212D-Y89A, M211 N-P212D-Y89A-M117A, M211 N-P212D-Y89A-M117F, M211 N-P212D-Y89A-M117I, M211 N-P212D-Y89A-M117L, M211 N-P212D-Y89A-M117V, M211 N-P212D-Y89A-M216A, M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 N-P212D-Y89A-M117A-M216A, M211 M211 N-P212D-Y89A-M117F-M216F, M211 N-P212D-Y89A-M117A-M216F, M211 N-P212D-Y89A-M117F-M216L, M211 N-P212D-Y89A-M117I-M216A, M211 N-P212D-Y89A-M117I-M216F, M211 N-P212D-Y89A-M117I-M216L, M211 N-P212D-Y89A-M117L-M216A, M211 N-P212D-Y89A-M117L-M216F, M211 N-P212D-Y89A-M117L-M216L, M211 N-P212D-Y89A-M117V-M216A, M211 N-P212D-Y89A-M117V-M216F, M211 N-P212D-Y89A-M117V-M216L, M211 N-P212D-M117A, M211 N-P212D-M117F, M211 N-P212D-M117I, M211 N-P212D-M117L, M211 N-P212D-M117V, M211 N-P212D- M117A-M216A, M211 N-P212D-M117A-M216F, M211 N-P212D-M117A-M216L, M211 N-P212D- M117F-M216A, M211 N-P212D-M117F-M216F, M211 M211 M211 N-P212D-M117L-M216F, M211 N-P212D-M117L-M216L, M211 N-P212D-M117V-M216A, M211 N-P212D-M117V-M216F, M211 N-P212D-M117V-M216L, M211 N-P212D-M216A, M211 N-P212D-M216F, M211 N-P212D-M216L, M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M117I, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G- M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M1171, M21 1 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D- A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M1171, M211 L-P212D-A29G-Y89A-M117L, M21 1 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M21 1 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D- A29G-D58P-Y89A-M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 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M211 L-P212D-D58P-Y89A-M1171, D127P-M211 L-P212D-D58P-Y89A-M117L, D127P-M211 L-P212D- D58P-Y89A-M117V, D127P-M211 L-P212D-D58P-Y89A-M216A, D127P-M211 L-P212D-D58P-Y89A- M216F, D127P-M211 L-P212D-D58P-Y89A-M216L, D127P-M211 L-P212D-D58P-M117A-M216A, D127P-M211 L-P212D-D58P-M117A-M216F, D127P-M211 L-P212D-D58P-M117A-M216L, D127P- M211 L-P212D-D58P-M117F-M216A, D127P-M211 L-P212D-D58P-M117F-M216F, D127P-M211 L- P212D-D58P-M117F-M216L, D127P-M211 L-P212D-D58P-M117I-M216A, D127P-M211 L-P212D- D58P-M117I-M216F, D127P-M211 L-P212D-D58P-M117I-M216L, D127P-M211 L-P212D-D58P- M117L-M216A, D127P-M211 L-P212D-D58P-M117L-M216F, D127P-M211 L-P212D-D58P-M117L- M216L, D127P-M211 L-P212D-D58P-M117V-M216A, D127P-M211 L-P212D-D58P-M117V-M216F, D127P-M211 L-P212D-D58P-M117V-M216L, D127P-M211 L-P212D-Y89A, D127P-M211 L-P212D- Y89A-M117A, D127P-M211 L-P212D-Y89A-M117F, D127P-M211 L-P212D-Y89A-M1171, D127P- M211 L-P212D-Y89A-M117L, D127P-M211 L-P212D-Y89A-M117V, D127P-M211 L-P212D-Y89A- M216A, D127P-M211 L-P212D-Y89A-M216F, D127P-M211 L-P212D-Y89A-M216L, D127P-M211 L- P212D-Y89A-M117A-M216A, D127P-M211 L-P212D-Y89A-M117A-M216F, D127P-M211 L-P212D- Y89A-M117A-M216L, D127P-M211 L-P212D-Y89A-M117F-M216A, D127P-M211 L-P212D-Y89A- M117F-M216F, D127P-M211 L-P212D-Y89A-M117F-M216L, D127P-M211 L-P212D-Y89A-M1171- M216A, D127P-M211 L-P212D-Y89A-M117I-M216F, D127P-M211 L-P212D-Y89A-M117I-M216L, D127P-M211 L-P212D-Y89A-M117L-M216A, D127P-M211 L-P212D-Y89A-M117L-M216F, D127P- M211 L-P212D-Y89A-M117L-M216L, D127P-M211 L-P212D-Y89A-M117V-M216A, D127P-M211 L- P212D-Y89A-M117V-M216F, D127P-M211 L-P212D-Y89A-M117V-M216L, D127P-M211 L-P212D- M117A, D127P-M211 L-P212D-M117F, D127P-M211 L-P212D-M1171, D127P-M211 L-P212D-M117L, D127P-M211 L-P212D-M117 V, D127P-M211 L-P212D-M117A-M216A, D127P-M211 L-P212D-M117A- M216F, D127P-M211 L-P212D-M117A-M216L, D127P-M211 L-P212D-M117F-M216A, D127P-M211 L- P212D-M117F-M216F, D127P-M211 L-P212D-M117F-M216L, D127P-M211 L-P212D-M117I-M216A, D127P-M211 L-P212D-M117I-M216F, D127P-M211 L-P212D-M117I-M216L, D127P-M211 L-P212D- M117L-M216A, D127P-M211 L-P212D-M117L-M216F, D127P-M211 L-P212D-M117L-M216L, D127P- M211 L-P212D-M117V-M216A, D127P-M211 L-P212D-M117V-M216F, D127P-M211 L-P212D-M117V- M216L, D127P-M211 L-P212D-M216A, D127P-M211 L-P212D-M216F, D127P-M211 L-P212D-M216L, P212H-A29G, P212H-A29G-D58P, P212H-A29G-Y89A, P212H-A29G-M117A, P212H-A29G-M117F, P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H- A29G-M216F, P212H-A29G-M216L, P212H-A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H- A29G-D58P-M117F, P212H-A29G-D58P-M1171, P212H-A29G-D58P-M117L, P212H-A29G-D58P- M117V, P212H-A29G-D58P-M216A, P212H-A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A-M117F, P212H-A29G-Y89A-M1171, P212H-A29G- Y89A-M117L, P212H-A29G-Y89A-M117V, P212H-A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A-M216A, P212H-A29G-M117A-M216F, P212H- A29G-M117A-M216L, P212H-A29G-D58P-Y89A-M117A, P212H-A29G-D58P-Y89A-M117F, P212H- A29G-D58P-Y89A-M1171, P212H-A29G-D58P-Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G-D58P-Y89A-M216F, P212H-A29G-D58P-Y89A- M216L, P212H-A29G-Y89A-M117A-M216A, P212H-A29G-Y89A-M117A-M216F, P212H-A29G-Y89A- M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H- A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M117I-M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A-M117L-M216A, P212H-A29G-Y89A-M117L- M216F, P212H-A29G-Y89A-M117L-M216L, P212H-A29G-Y89A-M117V-M216A, P212H-A29G-Y89A- M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P- M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H-D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M1171, P212H-D58P-Y89A-M117L, P212H-D58P- Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P-Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A-M216F, P212H-D58P-M117A-M216L, P212H- D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P- M117I-M216A, P212H-D58P-M117I-M216F, P212H-D58P-M117I-M216L, P212H-D58P-M117L- M216A, P212H-D58P-M117L-M216F, P212H-D58P-M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V-M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H-Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A- M216A, P212H-Y89A-M216F, P212H-Y89A-M216L, P212H-Y89A-M117A-M216A, P212H-Y89A- M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F- M216F, P212H-Y89A-M117F-M216L, P212H-Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L-M216A, P212H-Y89A-M117L-M216F, P212H- Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A- M117V-M216L, P212H-M117A, P212H-M117F, P212H-M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H-M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I-M216A, P212H-M117I-M216F, P212H- M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V- M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H- M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S-A29G-D58P, Q12L-M122L-A222S-A29G- Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L-A222S-A29G-M117F, Q12L-M122L-A222S- A29G-M117I, Q12L-M122L-A222S-A29G-M117L, Q12L-M122L-A222S-A29G-M117V, Q12L-M122L- A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L- M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S-A29G-D58P-M117A, Q12L-M122L-A222S- A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P-M117I, Q12L-M122L-A222S-A29G-D58P- M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L-M122L-A222S-A29G-D58P-M216A, Q12L- M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S-A29G-D58P-M216L, Q12L-M122L-A222S- A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A-M117F, Q12L-M122L-A222S-A29G-Y89A- M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L-M122L-A222S-A29G-Y89A-M117V, Q12L- M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S-A29G-Y89A-M216F, Q12L-M122L-A222S- A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A-M216A, Q12L-M122L-A222S-A29G-M117A- M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M1171, Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S-D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L-A222S-D58P-M1171, Q12L-M122L-A222S-D58P- M117L, Q12L-M122L-A222S-D58P-M117V, Q12L-M122L-A222S-D58P-M216A, Q12L-M122L-A222S- D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L- M122L-A222S-D58P-Y89A-M117F, Q12L-M122L-A222S-D58P-Y89A-M1171, Q12L-M122L-A222S- D58P-Y89A-M117L, Q12L-M122L-A222S-D58P-Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A- M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L- M122L-A222S-D58P-M117A-M216A, Q12L-M122L-A222S-D58P-M117A-M216F, Q12L-M122L- A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P-M117F-M216A, Q12L-M122L-A222S-D58P- M117F-M216F, Q12L-M122L-A222S-D58P-M117F-M216L, Q12L-M122L-A222S-D58P-M1171- M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L-M122L-A222S-D58P-M117I-M216L, Q12L- M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S-D58P-M117L-M216F, Q12L-M122L- A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V-M216A, Q12L-M122L-A222S-D58P- M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L- A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L- M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A-M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S-Y89A-M216L, Q12L-M122L-A222S-Y89A- M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A- M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L-A222S-Y89A-M117F-M216F, Q12L- M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A-M117I-M216A, Q12L-M122L-A222S- Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L- M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L-A222S-Y89A-M117L-M216L, Q12L- M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A-M117V-M216F, Q12L-M122L- A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L-M122L-A222S-M117F, Q12L- M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L-A222S-M117V, Q12L-M122L- A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L-M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F-M216F, Q12L-M122L-A222S- M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L-A222S-M117I-M216F, Q12L- M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L- M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S-M117V-M216A, Q12L-M122L- A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L-M122L-A222S-M216A, Q12L- M122L-A222S-M216F, Q12L-M122L-A222S-M216L bestehenden Gruppe ausgewählt ist. M211 L-P212D-D58P-Y89A-M1171, D127P-M211 L-P212D-D58P-Y89A-M117L, D127P-M211 L-P212D- D58P-Y89A-M117V, D127P-M211 L-P212D-D58P-Y89A-M216A, D127P-M211 L-P212D-D58P-Y89A-M216F, D127P-M211 L-P212D-D58P-Y89A-M216L, D127P-M211 L-P212D-D58P-M117A-M216A, D127P-M211 L-P212D-D58P-M117A-M216F, D127P-M211 L-P212D-D58P-M117A-M216L, D127P-M211 L-P212D-D58P-M117F-M216A, D127P-M211 L-P212D-D58P-M117F-M216F, D127P-M211 L- P212D-D58P-M117F-M216L, D127P-M211 L-P212D-D58P-M117I-M216A, D127P-M211 L-P212D- D58P-M117I-M216F, D127P-M211 L-P212D-D58P-M117I-M216L, D127P-M211 L-P212D-D58P-M117L-M216A, D127P-M211 L-P212D-D58P-M117L-M216F, D127P-M211 L-P212D-D58P-M117L- M216L, D127P-M211 L-P212D-D58P-M117V-M216A, D127P-M211 L-P212D-D58P-M117V-M216F, D127P-M211 L-P212D-D58P-M117V-M216L, D127P-M211 L-P212D-Y89A, D127P-M211 L-P212D- Y89A-M117A, D127P-M211 L-P212D-Y89A-M117F, D127P-M211 L-P212D-Y89A-M1171, D127P- M211 L-P212D-Y89A-M117L, D127P-M211 L-P212D-Y89A-M117V, D127P-M211 L-P212D-Y89A-M216A, D127P-M211 L-P212D-Y89A-M216F, D127P-M211 L-P212D-Y89A-M216L, D127P-M211 L- P212D-Y89A-M117A-M216A, D127P-M211 L-P212D-Y89A-M117A-M216F, D127P-M211 L-P212D- Y89A-M117A-M216L, D127P-M211 L-P212D-Y89A-M117F-M216A, D127P-M211 L-P212D-Y89A- M117F-M216F, D127P-M211 L-P212D-Y89A-M117F-M216L, D127P-M211 L-P212D-Y89A-M1171-M216A, D127P-M211 L-P212D-Y89A-M117I-M216F, D127P-M211 L-P212D-Y89A-M117I-M216L, D127P-M211 L-P212D-Y89A-M117L-M216A, D127P-M211 L-P212D-Y89A-M117L-M216F, D127P-M211 L-P212D-Y89A-M117L-M216L, D127P-M211 L-P212D-Y89A-M117V-M216A, D127P-M211 L- P212D-Y89A-M117V-M216F, D127P-M211 L-P212D-Y89A-M117V-M216L, D127P-M211 L-P212D- M117A, D127P-M211 L-P212D-M117F, D127P-M211 L-P212D-M1171, D127P-M211 L-P212D-M117L, D127P-M211 L-P212D-M117V, D127P-M211 L-P212D-M117A-M216A, D127P-M211 L-P212D-M117A- M216F, D127P-M211 L-P212D-M117A-M216L, D127P-M211 L-P212D-M117F-M216A, D127P-M211 L- P212D-M117F-M216F, D127P-M211 L-P212D-M117F-M216L, D127P-M211 L-P212D-M117I-M216A, D127P-M211 L-P212D-M117I-M216F, D127P-M211 L-P212D-M117I-M216L, D127P-M211 L-P212D-M117L-M216A, D127P-M211 L-P212D-M117L-M216F, D127P-M211 L-P212D-M117L-M216L, D127P-M211 L-P212D-M117V-M216A, D127P-M211 L-P212D-M117V-M216F, D127P-M211 L-P212D-M117V- M216L, D127P-M211 L-P212D-M216A, D127P-M211 L-P212D-M216F, D127P-M211 L-P212D-M216L, P212H-A29G, P212H-A29G-D58P, P212H-A29G-Y89A, P212H-A29G-M117A, P212H-A29G-M117F, P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H- A29G-M216F, P212H-A29G-M216L, P212H-A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H- A29G-D58P-M117F, P212H-A29G-D58P-M1171, P212H-A29G-D58P-M117L, P212H-A29G-D58P-M117V, P212H-A29G-D58P-M216A, P212H-A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A-M117F, P212H-A29G-Y89A-M1171, P212H-A29G-Y89A-M117L, P212H-A29G-Y89A-M117V, P212H-A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A-M216A, P212H-A29G-M117A-M216F, P212H-A29G-M117A-M216L, P212H-A29G-D58P-Y89A-M117A, P212H-A29G-D58P-Y89A-M117F, P212H-A29G-D58P-Y89A-M1171, P212H-A29G-D58P-Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G-D58P-Y89A-M216F, P212H-A29G-D58P-Y89A-M216L, P212H-A29G-Y89A-M117A-M216A, P212H-A29G-Y89A-M117A-M216F, P212H-A29G-Y89A-M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H-A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M117I-M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A-M117L-M216A, P212H-A29G-Y89A-M117L-M216F, P212H-A29G-Y89A-M117L-M216L, P212H-A29G-Y89A-M117V-M216A, P212H-A29G-Y89A- M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P-M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H-D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M1171, P212H-D58P-Y89A-M117L, P212H-D58P- Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P-Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A-M216F, P212H-D58P-M117A-M216L, P212H-D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P-M117I-M216A, P212H-D58P-M117I-M216F, P212H-D58P-M117I-M216L, P212H-D58P-M117L- M216A, P212H-D58P-M117L-M216F, P212H-D58P-M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V-M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H-Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A-M216A, P212H-Y89A-M216F, P212H-Y89A-M216L, P212H-Y89A-M117A-M216A, P212H-Y89A-M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F-M216F, P212H-Y89A-M117F-M216L, P212H-Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L-M216A, P212H-Y89A-M117L-M216F, P212H-Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A- M117V-M216L, P212H-M117A, P212H-M117F, P212H-M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H-M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I-M216A, P212H-M117I-M216F, P212H- M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V-M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H-M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S-A29G-D58P, Q12L-M122L-A222S-A29G-Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L-A222S-A29G-M117F, Q12L-M122L-A222S-A29G-M117I, Q12L-M122L-A222S-A29G-M117L, Q12L-M122L-A222S-A29G-M117V, Q12L-M122L-A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S-A29G-D58P-M117A, Q12L-M122L-A222S- A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P-M117I, Q12L-M122L-A222S-A29G-D58P- M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L-M122L-A222S-A29G-D58P-M216A, Q12L-M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S-A29G-D58P-M216L, Q12L-M122L-A222S- A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A-M117F, Q12L-M122L-A222S-A29G-Y89A-M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L-M122L-A222S-A29G-Y89A-M117V, Q12L-M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S-A29G-Y89A-M216F, Q12L-M122L-A222S- A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A-M216A, Q12L-M122L-A222S-A29G-M117A-M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M1171, Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S-D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L-A222S-D58P-M1171, Q12L-M122L-A222S-D58P-M117L, Q12L-M122L-A222S-D58P-M117V, Q12L-M122L-A222S-D58P-M216A, Q12L-M122L-A222S-D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L- M122L-A222S-D58P-Y89A-M117F, Q12L-M122L-A222S-D58P-Y89A-M1171, Q12L-M122L-A222S-D58P-Y89A-M117L, Q12L-M122L-A222S-D58P-Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A-M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L- M122L-A222S-D58P-M117A-M216A, Q12L-M122L-A222S-D58P-M117A-M216F, Q12L-M122L-A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P-M117F-M216A, Q12L-M122L-A222S-D58P-M117F-M216F, Q12L-M122L-A222S-D58P-M117F-M216L, Q12L-M122L-A222S-D58P-M1171-M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L-M122L-A222S-D58P-M117I-M216L, Q12L-M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S-D58P-M117L-M216F, Q12L-M122L- A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V-M216A, Q12L-M122L-A222S-D58P-M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L-A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L-M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A-M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S-Y89A-M216L, Q12L-M122L-A222S-Y89A-M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A-M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L-A222S-Y89A-M117F-M216F, Q12L- M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A-M117I-M216A, Q12L-M122L-A222S-Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L-M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L-A222S-Y89A-M117L-M216L, Q12L- M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A-M117V-M216F, Q12L-M122L-A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L-M122L-A222S-M117F, Q12L-M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L-A222S-M117V, Q12L-M122L-A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L-M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F-M216F, Q12L-M122L-A222S-M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L-A222S-M117I-M216F, Q12L-M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L- M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S-M117V-M216A, Q12L-M122L- A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L-M122L-A222S-M216A, Q12L- M122L-A222S-M216F, Q12L-M122L-A222S-M216L existing group selected is.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , eine Aminosäuresubstitutionskombination aufweist, die aus der aus M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L- P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D- A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G- M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P- M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D- A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L- P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A- M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D- A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G- D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A- M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L- P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G- D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A- M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L- P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G- Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L- M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L- P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P- M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L- P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M1171, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A- M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D- D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P- M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L- P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L- M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D- D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D- Y89A-M117A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A- M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A- M216F, M211 L-P212D-Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D- Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A- M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L- P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V- M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D- M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F- M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L- P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D- M216A, M211 L-P212D-M216F, M211 L-P212D-M216L bestehenden Gruppe ausgewählt ist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G- M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P- M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L- P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A- M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D- A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G- D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A- M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G- D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A- M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L- P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G- Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L- M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P- M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L-P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M1171, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A- M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L-P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L- M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D- D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D-Y89A-M117A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A- M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A- M216F, M211 L-P212D-Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V- M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D- M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F- M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L- P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D- M216A, M211 L-P212D-M216F, M211 L-P212D-M216L existing group is selected.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , eine Aminosäuresubstitutionskombination aufweist, die aus der aus M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V- M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D- M216F, D58P-M211 L-P212D-M216A und M211 L-P212D-M216L bestehenden Gruppe ausgewählt ist. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V- M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D- M216F, D58P-M211 L-P212D-M216A and M211 L-P212D-M216L existing group is selected.

In bevorzugten Ausführungsformen umfasst die erfindungsgemäße Protease eine Aminosäuresubstitutionskombination, die aus der aus I43V-A29G, I43V-A29G-D58P, I43V-A29G- Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M1171, I43V-A29G-M117L, I43V-A29G- M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V- A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M1171, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P-M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P- M216L, I43V-A29G-Y89A-M117A, I43V-A29G-Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G- Y89A-M117L, I43V-A29G-Y89A-M117V, I43V-A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V- A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A- M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G-D58P-Y89A-M117F, I43V-A29G-D58P-Y89A- M117I, I43V-A29G-D58P-Y89A-M117L, I43V-A29G-D58P-Y89A-M117V, I43V-A29G-D58P-Y89A- M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G-D58P-Y89A-M216L, I43V-A29G-Y89A-M117A- M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G-Y89A-M117A-M216L, I43V-A29G-Y89A- M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V-A29G-Y89A-M117F-M216L, I43V-A29G- Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V-A29G-Y89A-M117I-M216L, I43V-A29G- Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V-A29G-Y89A-M117L-M216L, I43V- A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P-M117F, I43V-D58P-M1171, I43V-D58P- M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P-M216F, I43V-D58P-M216L, I43V-D58P- Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A-M1171, I43V-D58P-Y89A-M117L, I43V- D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P-Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V-D58P-M117A-M216L, I43V-D58P- M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F-M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P-M117L-M216A, I43V-D58P-M117L- M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V- D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A-M117F, I43V-Y89A-M1171, I43V- Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A-M216F, I43V-Y89A-M216L, I43V- Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A-M117A-M216L, I43V-Y89A-M117F- M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V- Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L-M216A, I43V-Y89A-M117L- M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V-Y89A-M117V-M216F, I43V- Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V-M117L, I43V-M117V, I43V- M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F-M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V-M117I-M216L, I43V-M117L- M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V- M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S-T156A-A29G, M122L-N154S- T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S-T156A-A29G-M117A, M122L- N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M117I, M122L-N154S-T156A-A29G- M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A-A29G-M216A, M122L-N154S- T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L-N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A-A29G-D58P-M117F, M122L- N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P-M117L, M122L-N154S-T156A- A29G-D58P-M117V, M122L-N154S-T156A-A29G-D58P-M216A, M122L-N154S-T156A-A29G-D58P- M216F, M122L-N154S-T156A-A29G-D58P-M216L, M122L-N154S-T156A-A29G-Y89A-M117A, M122L-N154S-T156A-A29G-Y89A-M117F, M122L-N154S-T156A-A29G-Y89A-M117I, M122L-N154S- T156A-A29G-Y89A-M117L, M122L-N154S-T156A-A29G-Y89A-M117V, M122L-N154S-T156A-A29G- Y89A-M216A, M122L-N154S-T156A-A29G-Y89A-M216F, M122L-N154S-T156A-A29G-Y89A-M216L, M122L-N154S-T156A-A29G-M117A-M216A, M122L-N154S-T156A-A29G-M117A-M216F, M122L- N154S-T156A-A29G-M117A-M216L, M122L-N154S-T156A-A29G-D58P-Y89A-M117A, M122L- N154S-T156A-A29G-D58P-Y89A-M117F, M122L-N154S-T156A-A29G-D58P-Y89A-M117I, M122L- N154S-T156A-A29G-D58P-Y89A-M117L, M122L-N154S-T156A-A29G-D58P-Y89A-M117V, M122L- N154S-T156A-A29G-D58P-Y89A-M216A, M122L-N154S-T156A-A29G-D58P-Y89A-M216F, M122L- N154S-T156A-A29G-D58P-Y89A-M216L, M122L-N154S-T156A-A29G-Y89A-M117A-M216A, M122L- N154S-T156A-A29G-Y89A-M117A-M216F, M122L-N154S-T156A-A29G-Y89A-M117A-M216L, M122L-N154S-T156A-A29G-Y89A-M117F-M216A, M122L-N154S-T156A-A29G-Y89A-M117F- M216F, M122L-N154S-T156A-A29G-Y89A-M117F-M216L, M122L-N154S-T156A-A29G-Y89A-M117I- M216A, M122L-N154S-T156A-A29G-Y89A-M117I-M216F, M122L-N154S-T156A-A29G-Y89A-M117I- M216L, M122L-N154S-T156A-A29G-Y89A-M117L-M216A, M122L-N154S-T156A-A29G-Y89A- M117L-M216F, M122L-N154S-T156A-A29G-Y89A-M117L-M216L, M122L-N154S-T156A-A29G- Y89A-M117V-M216A, M122L-N154S-T156A-A29G-Y89A-M117V-M216F, M122L-N154S-T156A- A29G-Y89A-M117V-M216L, M122L-N154S-T156A-D58P, M122L-N154S-T156A-D58P-Y89A, M122L- N154S-T156A-D58P-M117A, M122L-N154S-T156A-D58P-M117F, M122L-N154S-T156A-D58P- M117I, M122L-N154S-T156A-D58P-M117L, M122L-N154S-T156A-D58P-M117V, M122L-N154S- T156A-D58P-M216A, M122L-N154S-T156A-D58P-M216F, M122L-N154S-T156A-D58P-M216L, M122L-N154S-T156A-D58P-Y89A-M117A, M122L-N154S-T156A-D58P-Y89A-M117F, M122L- N154S-T156A-D58P-Y89A-M117I, M122L-N154S-T156A-D58P-Y89A-M117L, M122L-N154S-T156A- D58P-Y89A-M117V, M122L-N154S-T156A-D58P-Y89A-M216A, M122L-N154S-T156A-D58P-Y89A- M216F, M122L-N154S-T156A-D58P-Y89A-M216L, M122L-N154S-T156A-D58P-M117A-M216A, M122L-N154S-T156A-D58P-M117A-M216F, M122L-N154S-T156A-D58P-M117A-M216L, M122L- N154S-T156A-D58P-M117F-M216A, M122L-N154S-T156A-D58P-M117F-M216F, M122L-N154S- T156A-D58P-M117F-M216L, M122L-N154S-T156A-D58P-M117I-M216A, M122L-N154S-T156A- D58P-M117I-M216F, M122L-N154S-T156A-D58P-M117I-M216L, M122L-N154S-T156A-D58P- M117L-M216A, M122L-N154S-T156A-D58P-M117L-M216F, M122L-N154S-T156A-D58P-M117L- M216L, M122L-N154S-T156A-D58P-M117V-M216A, M122L-N154S-T156A-D58P-M117V-M216F, M122L-N154S-T156A-D58P-M117V-M216L, M122L-N154S-T156A-Y89A, M122L-N154S-T156A- Y89A-M117A, M122L-N154S-T156A-Y89A-M117F, M122L-N154S-T156A-Y89A-M1171, M122L- N154S-T156A-Y89A-M117L, M122L-N154S-T156A-Y89A-M117V, M122L-N154S-T156A-Y89A- M216A, M122L-N154S-T156A-Y89A-M216F, M122L-N154S-T156A-Y89A-M216L, M122L-N154S- T156A-Y89A-M117A-M216A, M122L-N154S-T156A-Y89A-M117A-M216F, M122L-N154S-T156A- Y89A-M117A-M216L, M122L-N154S-T156A-Y89A-M117F-M216A, M122L-N 154S-T156A-Y89A- M117F-M216F, M122L-N154S-T156A-Y89A-M117F-M216L, M122L-N154S-T156A-Y89A-M117I- M216A, M122L-N154S-T156A-Y89A-M117I-M216F, M122L-N154S-T156A-Y89A-M117I-M216L, M122L-N154S-T156A-Y89A-M117L-M216A, M122L-N154S-T156A-Y89A-M117L-M216F, M122L- N 154S-T156A-Y89A-M 117L-M216L, M 122L-N 154S-T156A-Y89A-M 117V-M216A, M 122L-N 154S- T156A-Y89A-M117V-M216F, M122L-N154S-T156A-Y89A-M117V-M216L, M122L-N154S-T156A- M117A, M122L-N154S-T156A-M117F, M122L-N154S-T156A-M1171, M122L-N154S-T156A-M117L, M122L-N154S-T156A-M117V, M122L-N154S-T156A-M117A-M216A, M122L-N154S-T156A-M117A- M216F, M122L-N154S-T156A-M117A-M216L, M122L-N154S-T156A-M117F-M216A, M122L-N154S- T156A-M117F-M216F, M122L-N154S-T156A-M117F-M216L, M122L-N154S-T156A-M117I-M216A, M122L-N154S-T156A-M117I-M216F, M122L-N154S-T156A-M117I-M216L, M122L-N154S-T156A- M117L-M216A, M122L-N154S-T156A-M117L-M216F, M122L-N154S-T156A-M117L-M216L, M122L- N154S-T156A-M117V-M216A, M122L-N154S-T156A-M117V-M216F, M122L-N154S-T156A-M117V- M216L, M122L-N154S-T156A-M216A, M122L-N154S-T156A-M216F, M122L-N154S-T156A-M216L, M211 N-P212D-A29G, M211 N-P212D-A29G-D58P, M211 N-P212D-A29G-Y89A, M211 N-P212D- A29G-M117A, M211 N-P212D-A29G-M117F, M211 N-P212D-A29G-M117I, M211 N-P212D-A29G- M117L, M211 N-P212D-A29G-M117V, M211 N-P212D-A29G-M216A, M211 N-P212D-A29G-M216F, M211 N-P212D-A29G-M216L, M211 N-P212D-A29G-D58P-Y89A, M211 N-P212D-A29G-D58P-M117A, M211 N-P212D-A29G-D58P-M117F, M211 N-P212D-A29G-D58P-M117I, M211 N-P212D-A29G-D58P- M117L, M211 N-P212D-A29G-D58P-M117V, M211 N-P212D-A29G-D58P-M216A, M211 N-P212D- A29G-D58P-M216F, M211 N-P212D-A29G-D58P-M216L, M211 N-P212D-A29G-Y89A-M117A, M211 N-P212D-A29G-Y89A-M117F, M211 N-P212D-A29G-Y89A-M1171, M211 N-P212D-A29G-Y89A- M117L, M211 N-P212D-A29G-Y89A-M117V, M211 N-P212D-A29G-Y89A-M216A, M211 N-P212D- A29G-Y89A-M216F, M211 N-P212D-A29G-Y89A-M216L, M211 N-P212D-A29G-M117A-M216A, M211 N-P212D-A29G-M117A-M216F, M211 N-P212D-A29G-M117A-M216L, M211 N-P212D-A29G- D58P-Y89A-M117A, M211 N-P212D-A29G-D58P-Y89A-M117F, M211 N-P212D-A29G-D58P-Y89A- M117I, M211 N-P212D-A29G-D58P-Y89A-M117L, M211 N-P212D-A29G-D58P-Y89A-M117V, M211 N- P212D-A29G-D58P-Y89A-M216A, M211 N-P212D-A29G-D58P-Y89A-M216F, M211 N-P212D-A29G- D58P-Y89A-M216L, M211 N-P212D-A29G-Y89A-M117A-M216A, M211 N-P212D-A29G-Y89A-M117A- M216F, M211 N-P212D-A29G-Y89A-M117A-M216L, M211 N-P212D-A29G-Y89A-M117F-M216A, M211 N-P212D-A29G-Y89A-M117F-M216F, M211 N-P212D-A29G-Y89A-M117F-M216L, M211 N- P212D-A29G-Y89A-M117I-M216A, M211 N-P212D-A29— Y89A-M117I-M216F, M211 N-P212D-A29G- Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L-M216A, M211 N-P212D-A29G-Y89A-M117L- M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 N-P212D-A29G-Y89A-M117V-M216A, M211 N-P212D-A29G-Y89A-M117V-M216F, M211 N-P212D-A29— Y89A-M117V-M216L, M211 N- P212D-D58P, M211 N-P212D-D58P-Y89A, M211 N-P212D-D58P-M117A, M211 N-P212D-D58P- M117F, M211 N-P212D-D58P-M117I, M211 N-P212D-D58P-M117L, M211 N-P212D-D58P-M117V, M211 N-P212D-D58P-M216A, M211 N-P212D-D58P-M216F, M211 N-P212D-D58P-M216L, M211 N- P212D-D58P-Y89A-M117A, M211 N-P212D-D58P-Y89A-M117F, M211 N-P212D-D58P-Y89A-M117I, M211 N-P212D-D58P-Y89A-M117L, M211 N-P212D-D58P-Y89A-M117V, M211 N-P212D-D58P-Y89A- M216A, M211 N-P212D-D58P-Y89A-M216F, M211 N-P212D-D58P-Y89A-M216L, M211 N-P212D- D58P-M117A-M216A, M211 N-P212D-D58P-M117A-M216F, M211 N-P212D-D58P-M117A-M216L, M211 N-P212D-D58P-M117F-M216A, M211 N-P212D-D58P-M117F-M216F, M211 N-P212D-D58P- M117F-M216L, M211 N-P212D-D58P-M117I-M216A, M211 N-P212D-D58P-M117I-M216F, M211 N- P212D-D58P-M117I-M216L, M211 N-P212D-D58P-M117L-M216A, M211 N-P212D-D58P-M117L- M216F, M211 N-P212D-D58P-M117L-M216L, M211 N-P212D-D58P-M117V-M216A, M211 N-P212D- D58P-M117V-M216F, M211 N-P212D-D58P-M117V-M216L, M211 N-P212D-Y89A, M211 N-P212D- Y89A-M117A, M211 N-P212D-Y89A-M117F, M211 N-P212D-Y89A-M1171, M211 N-P212D-Y89A- M117L, M211 N-P212D-Y89A-M117V, M211 N-P212D-Y89A-M216A, M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 N-P212D-Y89A-M117A-M216A, M211 N-P212D-Y89A-M117A- M216F, M211 N-P212D-Y89A-M117A-M216L, M211 N-P212D-Y89A-M117F-M216A, M211 N-P212D- Y89A-M117F-M216F, M211 N-P212D-Y89A-M117F-M216L, M211 N-P212D-Y89A-M117I-M216A, M211 N-P212D-Y89A-M117I-M216F, M211 N-P212D-Y89A-M117I-M216L, M211 N-P212D-Y89A- M117L-M216A, M211 N-P212D-Y89A-M117L-M216F, M211 N-P212D-Y89A-M117L-M216L, M211 N- P212D-Y89A-M117V-M216A, M211 N-P212D-Y89A-M117V-M216F, M211 N-P212D-Y89A-M117V- M216L, M211 N-P212D-M117A, M211 N-P212D-M117F, M211 N-P212D-M117I, M211 N-P212D- M117L, M211 N-P212D-M117V, M211 N-P212D-M117A-M216A, M211 N-P212D-M117A-M216F, M211 N-P212D-M117A-M216L, M211 N-P212D-M117F-M216A, M211 N-P212D-M117F-M216F, M211 N-P212D-M117F-M216L, M211 N-P212D-M117I-M216A, M211 N-P212D-M117I-M216F, M211 N- P212D-M117I-M216L, M211 N-P212D-M117L-M216A, M211 N-P212D-M117L-M216F, M211 N-P212D- M117L-M216L, M211 N-P212D-M117V-M216A, M211 N-P212D-M117V-M216F, M211 N-P212D- M117V-M216L, M211 N-P212D-M216A, M211 N-P212D-M216F, M211 N-P212D-M216L, M211 L- P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L- P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D- A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D- A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L- P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A- M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A-M117L, M211 L-P212D-A29G- Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L- P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A- M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L- P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A-M1171, M211 L-P212D-A29G- D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A- M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L- P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A-M216F, M211 L-P212D- A29G-Y89A-M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A- M117F-M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L-P212D-A29G-Y89A-M117I- M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L-M216F, M211 L- P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D- A29G-Y89A-M117V-M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P-M117F, M211 L- P212D-D58P-M1171, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D- D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L-P212D-D58P- Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M1171, M211 L-P212D- D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L- P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P- M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L- P212D-D58P-M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L-P212D-D58P-M1171- M216L, M211 L-P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L-M216F, M211 L-P212D- D58P-M117L-M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D-Y89A-M117A, M211 L- P212D-Y89A-M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A-M117L, M211 L-P212D- Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A- M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A-M216F, M211 L-P212D- Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A- M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L- P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V- M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V-M216L, M211L-P212D- M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D-M117A-M216L, M211 L- P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D- M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L- M216A, M211 L-P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D-M216A, M211 L-P212D- M216F, M211 L-P212D-M216L, G160S-A29G, G160S-A29G-D58P, G160S-A29G-Y89A, G160S- A29G-M117A, G160S-A29G-M117F, G160S-A29G-M1171, G160S-A29G-M117L, G160S-A29G- M117V, G160S-A29G-M216A, G160S-A29G-M216F, G160S-A29G-M216L, G160S-A29G-D58P- Y89A, G160S-A29G-D58P-M117A, G160S-A29G-D58P-M117F, G160S-A29G-D58P-M1171, G160S- A29G-D58P-M117L, G160S-A29G-D58P-M117V, G160S-A29G-D58P-M216A, G160S-A29G-D58P- M216F, G160S-A29G-D58P-M216L, G160S-A29G-Y89A-M117A, G160S-A29G-Y89A-M117F, G160S-A29G-Y89A-M117I, G160S-A29G-Y89A-M117L, G160S-A29G-Y89A-M117V, G160S-A29G- Y89A-M216A, G160S-A29G-Y89A-M216F, G160S-A29G-Y89A-M216L, G160S-A29G-M117A-M216A, G160S-A29G-M117A-M216F, G160S-A29G-M117A-M216L, G160S-A29G-D58P-Y89A-M117A, G160S-A29G-D58P-Y89A-M117F, G160S-A29G-D58P-Y89A-M1171, G160S-A29G-D58P-Y89A- M117L, G160S-A29G-D58P-Y89A-M117V, G160S-A29G-D58P-Y89A-M216A, G160S-A29G-D58P- Y89A-M216F, G160S-A29G-D58P-Y89A-M216L, G160S-A29G-Y89A-M117A-M216A, G160S-A29G- Y89A-M117A-M216F, G160S-A29G-Y89A-M117A-M216L, G160S-A29G-Y89A-M117F-M216A, G160S-A29G-Y89A-M117F-M216F, G160S-A29G-Y89A-M117F-M216L, G160S-A29G-Y89A-M1171- M216A, G160S-A29G-Y89A-M117I-M216F, G160S-A29G-Y89A-M117I-M216L, G160S-A29G-Y89A- M117L-M216A, G160S-A29G-Y89A-M117L-M216F, G160S-A29G-Y89A-M117L-M216L, G160S- A29G-Y89A-M117V-M216A, G160S-A29G-Y89A-M117V-M216F, G160S-A29G-Y89A-M117V-M216L, G160S-D58P, G160S-D58P-Y89A, G160S-D58P-M117A, G160S-D58P-M117F, G160S-D58P-M1171, G160S-D58P-M117L, G160S-D58P-M117V, G160S-D58P-M216A, G160S-D58P-M216F, G160S- D58P-M216L, G160S-D58P-Y89A-M117A, G160S-D58P-Y89A-M117F, G160S-D58P-Y89A-M1171, G160S-D58P-Y89A-M117L, G160S-D58P-Y89A-M117V, G160S-D58P-Y89A-M216A, G160S-D58P- Y89A-M216F, G160S-D58P-Y89A-M216L, G160S-D58P-M117A-M216A, G160S-D58P-M117A- M216F, G160S-D58P-M117A-M216L, G160S-D58P-M117F-M216A, G160S-D58P-M117F-M216F, G160S-D58P-M117F-M216L, G160S-D58P-M117I-M216A, G160S-D58P-M117I-M216F, G160S- D58P-M117I-M216L, G160S-D58P-M117L-M216A, G160S-D58P-M117L-M216F, G160S-D58P- M117L-M216L, G160S-D58P-M117V-M216A, G160S-D58P-M117V-M216F, G160S-D58P-M117V- M216L, G160S-Y89A, G160S-Y89A-M117A, G160S-Y89A-M117F, G160S-Y89A-M1171, G160S- Y89A-M117L, G160S-Y89A-M117V, G160S-Y89A-M216A, G160S-Y89A-M216F, G160S-Y89A- M216L, G160S-Y89A-M117A-M216A, G160S-Y89A-M117A-M216F, G160S-Y89A-M117A-M216L, G160S-Y89A-M117F-M216A, G160S-Y89A-M117F-M216F, G160S-Y89A-M117F-M216L, G160S- Y89A-M117I-M216A, G160S-Y89A-M117I-M216F, G160S-Y89A-M117I-M216L, G160S-Y89A-M117L- M216A, G160S-Y89A-M117L-M216F, G160S-Y89A-M117L-M216L, G160S-Y89A-M117V-M216A, G160S-Y89A-M117V-M216F, G160S-Y89A-M117V-M216L, G160S-M117A, G160S-M117F, G160S- M117I, G160S-M117L, G160S-M117V, G160S-M117A-M216A, G160S-M117A-M216F, G160S- M117A-M216L, G160S-M117F-M216A, G160S-M117F-M216F, G160S-M117F-M216L, G160S- M117I-M216A, G160S-M117I-M216F, G160S-M117I-M216L, G160S-M117L-M216A, G160S-M117L- M216F, G160S-M117L-M216L, G160S-M117V-M216A, G160S-M117V-M216F, G160S-M117V- M216L, G160S-M216A, G160S-M216F, G160S-M216L, D127P-M211 L-P212D-A29G, D127P-M211 L- P212D-A29G-D58P, D127P-M211 L-P212D-A29G-Y89A, D127P-M211 L-P212D-A29G-M117A, D127P-M211 L-P212D-A29G-M117F, D127P-M211 L-P212D-A29G-M1171, D127P-M211 L-P212D- A29G-M117L, D127P-M211 L-P212D-A29G-M117V, D127P-M211 L-P212D-A29G-M216A, D127P- M211 L-P212D-A29G-M216F, D127P-M211 L-P212D-A29G-M216L, D127P-M211 L-P212D-A29G- D58P-Y89A, D127P-M211 L-P212D-A29G-D58P-M117A, D127P-M211 L-P212D-A29G-D58P-M117F, D127P-M211 L-P212D-A29G-D58P-M1171, D127P-M211 L-P212D-A29G-D58P-M117L, D127P- M211 L-P212D-A29G-D58P-M117V, D127P-M211 L-P212D-A29G-D58P-M216A, D127P-M211 L- P212D-A29G-D58P-M216F, D127P-M211 L-P212D-A29G-D58P-M216L, D127P-M211 L-P212D- A29G-Y89A-M117A, D127P-M211 L-P212D-A29G-Y89A-M117F, D127P-M211 L-P212D-A29G-Y89A- M117I, D127P-M211 L-P212D-A29G-Y89A-M117L, D127P-M211 L-P212D-A29G-Y89A-M117V, D127P-M211 L-P212D-A29G-Y89A-M216A, D127P-M211 L-P212D-A29G-Y89A-M216F, D127P- M211 L-P212D-A29G-Y89A-M216L, D127P-M211 L-P212D-A29G-M117A-M216A, D127P-M211 L- P212D-A29G-M117A-M216F, D127P-M211 L-P212D-A29G-M117A-M216L, D127P-M211 L-P212D- A29G-D58P-Y89A-M117A, D127P-M211 L-P212D-A29G-D58P-Y89A-M117F, D127P-M211 L-P212D- A29G-D58P-Y89A-M1171, D127P-M211 L-P212D-A29G-D58P-Y89A-M117L, D127P-M211 L-P212D- A29G-D58P-Y89A-M117V, D127P-M211 L-P212D-A29G-D58P-Y89A-M216A, D127P-M211 L-P212D- A29G-D58P-Y89A-M216F, D127P-M211 L-P212D-A29G-D58P-Y89A-M216L, D127P-M211 L-P212D- A29G-Y89A-M117A-M216A, D127P-M211 L-P212D-A29G-Y89A-M117A-M216F, D127P-M211 L- P212D-A29G-Y89A-M117A-M216L, D127P-M211 L-P212D-A29G-Y89A-M117F-M216A, D127P- M211 L-P212D-A29G-Y89A-M117F-M216F, D127P-M211 L-P212D-A29G-Y89A-M117F-M216L, D127P-M211 L-P212D-A29G-Y89A-M117I-M216A, D127P-M211 L-P212D-A29— Y89A-M117I-M216F, D127P-M211 L-P212D-A29G-Y89A-M117I-M216L, D127P-M211 L-P212D-A29G-Y89A-M117L-M216A, D127P-M211 L-P212D-A29G-Y89A-M117L-M216F, D127P-M211 L-P212D-A29G-Y89A-M117L- M216L, D127P-M211 L-P212D-A29G-Y89A-M117V-M216A, D127P-M211 L-P212D-A29G-Y89A- M117V-M216F, D127P-M211 L-P212D-A29G-Y89A-M117V-M216L, D127P-M211 L-P212D-D58P, D127P-M211 L-P212D-D58P-Y89A, D127P-M211 L-P212D-D58P-M117A, D127P-M211 L-P212D- D58P-M117F, D127P-M211 L-P212D-D58P-M117I, D127P-M211 L-P212D-D58P-M117L, D127P- M211 L-P212D-D58P-M117V, D127P-M211 L-P212D-D58P-M216A, D127P-M211 L-P212D-D58P- M216F, D127P-M211 L-P212D-D58P-M216L, D127P-M211 L-P212D-D58P-Y89A-M117A, D127P- M211 L-P212D-D58P-Y89A-M117F, D127P-M211 L-P212D-D58P-Y89A-M117I, D127P-M211 L- P212D-D58P-Y89A-M117L, D127P-M211 L-P212D-D58P-Y89A-M117V, D127P-M211 L-P212D-D58P- Y89A-M216A, D127P-M211 L-P212D-D58P-Y89A-M216F, D127P-M211 L-P212D-D58P-Y89A-M216L, D127P-M211 L-P212D-D58P-M117A-M216A, D127P-M211 L-P212D-D58P-M117A-M216F, D127P- M211 L-P212D-D58P-M117A-M216L, D127P-M211 L-P212D-D58P-M117F-M216A, D127P-M211 L- P212D-D58P-M117F-M216F, D127P-M211 L-P212D-D58P-M117F-M216L, D127P-M211 L-P212D- D58P-M117I-M216A, D127P-M211 L-P212D-D58P-M117I-M216F, D127P-M211 L-P212D-D58P- M117I-M216L, D127P-M211 L-P212D-D58P-M117L-M216A, D127P-M211 L-P212D-D58P-M117L- M216F, D127P-M211 L-P212D-D58P-M117L-M216L, D127P-M211 L-P212D-D58P-M117V-M216A, D127P-M211 L-P212D-D58P-M117V-M216F, D127P-M211 L-P212D-D58P-M117V-M216L, D127P- M211 L-P212D-Y89A, D127P-M211 L-P212D-Y89A-M117A, D127P-M211 L-P212D-Y89A-M117F, D127P-M211 L-P212D-Y89A-M1171, D127P-M211 L-P212D-Y89A-M117L, D127P-M211 L-P212D- Y89A-M117V, D127P-M211 L-P212D-Y89A-M216A, D127P-M211 L-P212D-Y89A-M216F, D127P- M211 L-P212D-Y89A-M216L, D127P-M211 L-P212D-Y89A-M117A-M216A, D127P-M211 L-P212D- Y89A-M117A-M216F, D127P-M211 L-P212D-Y89A-M117A-M216L, D127P-M211 L-P212D-Y89A- M117F-M216A, D127P-M211 L-P212D-Y89A-M117F-M216F, D127P-M211 L-P212D-Y89A-M117F- M216L, D127P-M211 L-P212D-Y89A-M117I-M216A, D127P-M211 L-P212D-Y89A-M117I-M216F, D127P-M211 L-P212D-Y89A-M117I-M216L, D127P-M211 L-P212D-Y89A-M117L-M216A, D127P- M211 L-P212D-Y89A-M117L-M216F, D127P-M211 L-P212D-Y89A-M117L-M216L, D127P-M211 L- P212D-Y89A-M117V-M216A, D127P-M211 L-P212D-Y89A-M117V-M216F, D127P-M211 L-P212D- Y89A-M117V-M216L, D127P-M211 L-P212D-M117A, D127P-M211 L-P212D-M117F, D127P-M211 L- P212D-M117I, D127P-M211 L-P212D-M117L, D127P-M211 L-P212D-M117V, D127P-M211L-P212D- M117A-M216A, D127P-M211 L-P212D-M117A-M216F, D127P-M211 L-P212D-M117A-M216L, D127P- M211 L-P212D-M117F-M216A, D127P-M211 L-P212D-M117F-M216F, D127P-M211 L-P212D-M117F- M216L, D127P-M211 L-P212D-M117I-M216A, D127P-M211 L-P212D-M117I-M216F, D127P-M211 L- P212D-M117I-M216L, D127P-M211 L-P212D-M117L-M216A, D127P-M211 L-P212D-M117L-M216F, D127P-M211 L-P212D-M117L-M216L, D127P-M211 L-P212D-M117V-M216A, D127P-M211 L-P212D- M117V-M216F, D127P-M211 L-P212D-M117V-M216L, D127P-M211 L-P212D-M216A, D127P-M211 L- P212D-M216F, D127P-M211 L-P212D-M216L, P212H-A29G, P212H-A29G-D58P, P212H-A29G- Y89A, P212H-A29G-M117A, P212H-A29G-M117F, P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H-A29G-M216F, P212H-A29G-M216L, P212H- A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H-A29G-D58P-M117F, P212H-A29G-D58P- M117I, P212H-A29G-D58P-M117L, P212H-A29G-D58P-M117V, P212H-A29G-D58P-M216A, P212H- A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A- M117F, P212H-A29G-Y89A-M1171, P212H-A29G-Y89A-M117L, P212H-A29G-Y89A-M117V, P212H- A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A- M216A, P212H-A29G-M117A-M216F, P212H-A29G-M117A-M216L, P212H-A29G-D58P-Y89A- M117A, P212H-A29G-D58P-Y89A-M117F, P212H-A29G-D58P-Y89A-M117I, P212H-A29G-D58P- Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G- D58P-Y89A-M216F, P212H-A29G-D58P-Y89A-M216L, P212H-A29G-Y89A-M117A-M216A, P212H- A29G-Y89A-M117A-M216F, P212H-A29G-Y89A-M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H-A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M1171- M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A- M117L-M216A, P212H-A29G-Y89A-M117L-M216F, P212H-A29G-Y89A-M117L-M216L, P212H- A29G-Y89A-M117V-M216A, P212H-A29G-Y89A-M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P-M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H- D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M117I, P212H-D58P-Y89A-M117L, P212H-D58P-Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P- Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A- M216F, P212H-D58P-M117A-M216L, P212H-D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P-M117I-M216A, P212H-D58P-M117I-M216F, P212H- D58P-M117I-M216L, P212H-D58P-M117L-M216A, P212H-D58P-M117L-M216F, P212H-D58P- M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V- M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H- Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A-M216A, P212H-Y89A-M216F, P212H-Y89A- M216L, P212H-Y89A-M117A-M216A, P212H-Y89A-M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F-M216F, P212H-Y89A-M117F-M216L, P212H- Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L- M216A, P212H-Y89A-M117L-M216F, P212H-Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A-M117V-M216L, P212H-M117A, P212H-M117F, P212H- M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H- M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I- M216A, P212H-M117I-M216F, P212H-M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V-M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H-M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S- A29G-D58P, Q12L-M122L-A222S-A29G-Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L- A222S-A29G-M117F, Q12L-M122L-A222S-A29G-M1171, Q12L-M122L-A222S-A29G-M117L, Q12L- M122L-A222S-A29G-M117V, Q12L-M122L-A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S- A29G-D58P-M117A, Q12L-M122L-A222S-A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P- M117I, Q12L-M122L-A222S-A29G-D58P-M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L- M122L-A222S-A29G-D58P-M216A, Q12L-M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S- A29G-D58P-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A- M117F, Q12L-M122L-A222S-A29G-Y89A-M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L- M122L-A222S-A29G-Y89A-M117V, Q12L-M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S- A29G-Y89A-M216F, Q12L-M122L-A222S-A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A- M216A, Q12L-M122L-A222S-A29G-M117A-M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M117I , Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S- D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L- A222S-D58P-M1171, Q12L-M122L-A222S-D58P-M117L, Q12L-M122L-A222S-D58P-M117V, Q12L- M122L-A222S-D58P-M216A, Q12L-M122L-A222S-D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L-M122L-A222S-D58P-Y89A-M117F, Q12L-M122L- A222S-D58P-Y89A-M1171, Q12L-M122L-A222S-D58P-Y89A-M117L, Q12L-M122L-A222S-D58P- Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A-M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L-M122L-A222S-D58P-M117A-M216A, Q12L-M122L- A222S-D58P-M117A-M216F, Q12L-M122L-A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P- M117F-M216A, Q12L-M122L-A222S-D58P-M117F-M216F, Q12L-M122L-A222S-D58P-M117F- M216L, Q12L-M122L-A222S-D58P-M117I-M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L- M122L-A222S-D58P-M117I-M216L, Q12L-M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S- D58P-M117L-M216F, Q12L-M122L-A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V- M216A, Q12L-M122L-A222S-D58P-M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L-A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L-M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A- M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S- Y89A-M216L, Q12L-M122L-A222S-Y89A-M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A-M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L- A222S-Y89A-M117F-M216F, Q12L-M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A- M117I-M216A, Q12L-M122L-A222S-Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L-M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L- A222S-Y89A-M117L-M216L, Q12L-M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A- M117V-M216F, Q12L-M122L-A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L- M122L-A222S-M117F, Q12L-M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L- A222S-M117V, Q12L-M122L-A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L- M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F- M216F, Q12L-M122L-A222S-M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L- A222S-M117I-M216F, Q12L-M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L-M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S- M117V-M216A, Q12L-M122L-A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L- M122L-A222S-M216A, Q12L-M122L-A222S-M216F, Q12L-M122L-A222S-M216L bestehenden Gruppe ausgewählt ist, wobei die Nummerierung jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 ist und wobei die Protease neben den genannten Aminosäuresubstitutionen keine weiteren Änderungen umfasst. In preferred embodiments, the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M1171, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P-M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P- M216L, I43V-A29G-Y89A-M117A, I43V-A29G-Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G- Y89A-M117L, I43V-A29G-Y89A-M117V, I43V-A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V-A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A- M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G-D58P-Y89A-M117F, I43V-A29G-D58P-Y89A- M117I, I43V-A29G-D58P-Y89A-M117L, I43V-A29G-D58P-Y89A-M117V, I43V-A29G-D58P-Y89A-M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G-D58P-Y89A-M216L, I43V-A29G-Y89A-M117A-M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G-Y89A-M117A-M216L, I43V-A29G-Y89A-M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V-A29G-Y89A-M117F-M216L, I43V-A29G-Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V-A29G-Y89A-M117I-M216L, I43V-A29G- Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V-A29G-Y89A-M117L-M216L, I43V- A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P-M117F, I43V-D58P-M1171, I43V-D58P-M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P-M216F, I43V-D58P-M216L, I43V-D58P-Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A-M1171, I43V-D58P-Y89A-M117L, I43V-D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P-Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V-D58P-M117A-M216L, I43V-D58P- M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F-M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P-M117L-M216A, I43V-D58P-M117L- M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V- D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A-M117F, I43V-Y89A-M1171, I43V-Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A-M216F, I43V-Y89A-M216L, I43V- Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A-M117A-M216L, I43V-Y89A-M117F- M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V- Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L-M216A, I43V-Y89A-M117L-M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V-Y89A-M117V-M216F, I43V-Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V-M117L, I43V-M117V, I43V-M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F-M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V-M117I-M216L, I43V-M117L-M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V-M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S-T156A-A29G, M122L-N154S-T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S-T156A-A29G-M117A, M122L-N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M117I, M122L-N154S-T156A-A29G-M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A-A29G-M216A, M122L-N154S-T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L-N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A-A29G-D58P-M117F, M122L- N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P-M117L, M122L-N154S-T156A- A29G-D58P-M117V, M122L-N154S-T156A-A29G-D58P-M216A, M122L-N154S-T156A-A29G-D58P-M216F, M122L-N154S-T156A-A29G-D58P-M216L, M122L-N154S-T156A-A29G-Y89A-M117A, M122L-N154S-T156A-A29G-Y89A-M117F, M122L-N154S-T156A-A29G-Y89A-M117I, M122L-N154S-T156A-A29G-Y89A-M117L, M122L-N154S-T156A-A29G-Y89A-M117V, M122L-N154S-T156A-A29G-Y89A-M216A, M122L-N154S-T156A-A29G-Y89A-M216F, M122L-N154S-T156A-A29G-Y89A-M216L, M122L-N154S-T156A-A29G-M117A-M216A, M122L-N154S-T156A-A29G-M117A-M216F, M122L-N154S-T156A-A29G-M117A-M216L, M122L-N154S-T156A-A29G-D58P-Y89A-M117A, M122L-N154S-T156A-A29G-D58P-Y89A-M117F, M122L-N154S-T156A-A29G-D58P-Y89A-M117I, M122L N154S-T156A-A29G-D58P-Y89A-M117L, M122L-N154S-T156A-A29G-D58P-Y89A-M117V, M122L-N154S-T156A-A29G-D58P-Y89A-M216A, M122L-N154S-T156A-A29G-D58P-Y89A-M216F, M122L-N154S-T156A-A29G-D58P-Y89A-M216L, M122L-N154S-T156A-A29G-Y89A-M117A-M216A, M122L N154S-T156A-A29G-Y89A-M117A-M216F, M122L-N154S-T156A-A29G-Y89A-M117A-M216L, M122L-N154S-T156A-A29G-Y89A-M117F-M216A, M122L-N154S-T156A-A29G-Y89A-M117F- M216F, M122L-N154S-T156A-A29G-Y89A-M117F-M216L, M122L-N154S-T156A-A29G-Y89A-M117I- M216A, M122L-N154S-T156A-A29G-Y89A-M117I-M216F, M122L-N154S-T156A-A29G-Y89A-M117I-M216L, M122L-N154S-T156A-A29G-Y89A-M117L-M216A, M122L-N154S-T156A-A29G-Y89A-M117L-M216F, M122L-N154S-T156A-A29G-Y89A-M117L-M216L, M122L-N154S-T156A-A29G-Y89A-M117V-M216A, M122L-N154S-T156A-A29G-Y89A-M117V-M216F, M122L-N154S-T156A- A29G-Y89A-M117V-M216L, M122L-N154S-T156A-D58P, M122L-N154S-T156A-D58P-Y89A, M122L-N154S-T156A-D58P-M117A, M122L-N154S-T156A-D58P-M117F, M122L-N154S-T156A-D58P-M117I, M122L-N154S-T156A-D58P-M117L, M122L-N154S-T156A-D58P-M117V, M122L-N154S-T156A-D58P-M216A, M122L-N154S-T156A-D58P-M216F, M122L-N154S-T156A-D58P-M216L, M122L-N154S-T156A-D58P-Y89A-M117A, M122L-N154S-T156A-D58P-Y89A-M117F, M122L- N154S-T156A-D58P-Y89A-M117I, M122L-N154S-T156A-D58P-Y89A-M117L, M122L-N154S-T156A- D58P-Y89A-M117V, M122L-N154S-T156A-D58P-Y89A-M216A, M122L-N154S-T156A-D58P-Y89A-M216F, M122L-N154S-T156A-D58P-Y89A-M216L, M122L-N154S-T156A-D58P-M117A-M216A, M122L-N154S-T156A-D58P-M117A-M216F, M122L-N154S-T156A-D58P-M117A-M216L, M122L-N154S-T156A-D58P-M117F-M216A, M122L-N154S-T156A-D58P-M117F-M216F, M122L-N154S- T156A-D58P-M117F-M216L, M122L-N154S-T156A-D58P-M117I-M216A, M122L-N154S-T156A-D58P-M117I-M216F, M122L-N154S-T156A-D58P-M117I-M216L, M122L-N154S-T156A-D58P-M117L-M216A, M122L-N154S-T156A-D58P-M117L-M216F, M122L-N154S-T156A-D58P-M117L-M216L, M122L-N154S-T156A-D58P-M117V-M216A, M122L-N154S-T156A-D58P-M117V-M216F, M122L-N154S-T156A-D58P-M117V-M216L, M122L-N154S-T156A-Y89A, M122L-N154S-T156A- Y89A-M117A, M122L-N154S-T156A-Y89A-M117F, M122L-N154S-T156A-Y89A-M1171, M122L- N154S-T156A-Y89A-M117L, M122L-N154S-T156A-Y89A-M117V, M122L-N154S-T156A-Y89A- M216A, M122L-N154S-T156A-Y89A-M216F, M122L-N154S-T156A-Y89A-M216L, M122L-N154S-T156A-Y89A-M117A-M216A, M122L-N154S-T156A-Y89A-M117A-M216F, M122L-N154S-T156A-Y89A-M117A-M216L, M122L-N154S-T156A-Y89A-M117F-M216A, M122L-N 154S-T156A-Y89A- M117F-M216F, M122L-N154S-T156A-Y89A-M117F-M216L, M122L-N154S-T156A-Y89A-M117I- M216A, M122L-N154S-T156A-Y89A-M117I-M216F, M122L-N154S-T156A-Y89A-M117I-M216L, M122L-N154S-T156A-Y89A-M117L-M216A, M122L-N154S-T156A-Y89A-M117L-M216F, M122L-N 154S-T156A-Y89A-M 117L-M216L, M 122L-N 154S-T156A-Y89A-M 117V-M216A, M 122L-N 154S-T156A-Y89A-M117V-M216F, M122L-N154S-T156A-Y89A-M117V-M216L, M122L-N154S-T156A-M117A, M122L-N154S-T156A-M117F, M122L-N154S-T156A-M1171, M122L-N154S-T156A-M117L, M122L-N154S-T156A-M117V, M122L-N154S-T156A-M117A-M216A, M122L-N154S-T156A-M117A- M216F, M122L-N154S-T156A-M117A-M216L, M122L-N154S-T156A-M117F-M216A, M122L-N154S- T156A-M117F-M216F, M122L-N154S-T156A-M117F-M216L, M122L-N154S-T156A-M117I-M216A, M122L-N154S-T156A-M117I-M216F, M122L-N154S-T156A-M117I-M216L, M122L-N154S-T156A- M117L-M216A, M122L-N154S-T156A-M117L-M216F, M122L-N154S-T156A-M117L-M216L, M122L-N154S-T156A-M117V-M216A, M122L-N154S-T156A-M117V-M216F, M122L-N154S-T156A-M117V- M216L, M122L-N154S-T156A-M216A, M122L-N154S-T156A-M216F, M122L-N154S-T156A-M216L, M211 N-P212D-A29G, M211 N-P212D-A29G-D58P, M211 N-P212D-A29G-Y89A, M211 N-P212D-A29G-M117A, M211 N-P212D-A29G-M117F, M211 M211 N-P212D-A29G-M216F, M211 N-P212D-A29G-M216L, M211 N-P212D-A29G-D58P-Y89A, M211 N-P212D-A29G-D58P-M117A, M211 N-P212D-A29G-D58P-M117F, M211 N-P212D-A29G-D58P-M117I, M211 N-P212D-A29G-D58P- M117L, M211 N-P212D-A29G-D58P-M117V, M211 N-P212D-A29G-D58P-M216A, M211 N-P212D- A29G-D58P-M216F, M211 N-P212D-A29G-D58P-M216L, M211 N-P212D-A29G-Y89A-M117A, M211 N-P212D-A29G-Y89A-M117F, M211 N-P212D-A29G-Y89A-M1171, M211 N-P212D-A29G-Y89A- M117L, M211 N-P212D-A29G-Y89A-M117V, M211 N-P212D-A29G-Y89A-M216A, M211 N-P212D-A29G-Y89A-M216F, M211 M211 N-P212D-A29G-M117A-M216L, M211 N-P212D-A29G-M117A-M216L, M211 N-P212D-A29G-D58P-Y89A-M117A, M211 N-P212D-A29G-D58P-Y89A-M117F, M211 N-P212D-A29G-D58P-Y89A-M117I, M211 N-P212D-A29G-D58P-Y89A-M117L, M211 N-P212D-A29G-D58P-Y89A-M117V, M211 D58P-Y89A-M216L, M211 N-P212D-A29G-Y89A-M117A-M216A, M211 N-P212D-A29G-Y89A-M117A-M216F, M211 N-P212D-A29G-Y89A-M117A-M216L, M211 N-P212D-A29G-Y89A-M117F-M216A, M211 N-P212D-A29G-Y89A-M117F-M216F, M211 N-P212D-A29G-Y89A-M117F-M216L, M211 N- P212D-A29G-Y89A-M117I-M216A, M211 N-P212D-A29— Y89A-M117I-M216F, M211 N-P212D-A29G- Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L-M216A, M211 N-P212D-A29G-Y89A-M117L- M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 N-P212D-A29G-Y89A-M117V-M216A, M211 N-P212D-A29G-Y89A-M117V-M216F, M211 N-P212D-A29— Y89A-M117V-M216L, M211N- P212D-D58P, M211 M211 N-P212D-D58P-M117F M211 N-P212D-D58P-M216F M211 M211 N-P212D-D58P-Y89A-M117V, M211 N-P212D-D58P-Y89A-M117F, M211 M211 N-P212D-D58P-M117F-M216F, M211 N-P212D-D58P-M117F-M216F, M211 N-P212D-D58P-M117A-M216F, M211 M211 M211 N-P212D-D58P-M117L-M216A, M211 N-P212D - D58P - M117V - M216F, M211 N - P212D - D58P - M117V - M216L , M211 N - P212D - Y89A , M211 M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 N-P212D-Y89A-M117A-M216A, M211 N-P212D-Y89A-M117A-M216F, M211 N-P212D-Y89A-M117A-M216L, M211 M211 M211 N-P212D-Y89A-M117L-M216F, M211 M211 N-P212D-M117A, M211 N-P212D-M117F, M211 N-P212D-M117I, M211 N-P212D-M117L, M211 N-P212D-M117V, M211 N-P212D-M117A-M216A, M211 M211 N-P212D-M117F-M216L, M211 N-P212D-M117F-M216L, M211 N-P212D-M117I-M216A, M211 N-P212D-M117I-M216F, M211 N-P212D-M117I-M216L, M211 N-P212D-M117L-M216A, M211 N-P212D-M117L-M216F, M211 M211 N-P212D-M216F, M211 N-P212D-M216L, M211 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A29G-D58P-Y89A-M117A, D127P-M211 L-P212D-A29G-D58P-Y89A-M117F, D127P-M211 L-P212D-A29G-D58P-Y89A-M1171, D127P-M211 L-P212D-A29G-D58P-Y89A-M117L, D127P-M211 L-P212D- A29G-D58P-Y89A-M117V, D127P-M211 L-P212D-A29G-D58P-Y89A-M216A, D127P-M211 L-P212D- A29G-D58P-Y89A-M216F, D127P-M211 L-P212D-A29G-D58P-Y89A-M216L, D127P-M211 L-P212D- A29G-Y89A-M117A-M216A, D127P-M211 L-P212D-A29G-Y89A-M117A-M216F, D127P-M211 L- P212D-A29G-Y89A-M117A-M216L, D127P-M211 L-P212D-A29G-Y89A-M117F-M216A, D127P- M211 L-P212D-A29G-Y89A-M117F-M216F, D127P-M211 L-P212D-A29G-Y89A-M117F-M216L, D127P-M211 L-P212D-A29G-Y89A-M117I-M216A, D127P-M211 L-P212D-A29—Y89A-M117I-M216F, D127P-M211 L-P212D-A29G-Y89A-M117I-M216L, D127P-M211 L-P212D-A29G-Y89A-M117L-M216A, D127P-M211 L-P212D-A29G-Y89A-M117L-M216F, D127P-M211 L-P212D-A29G-Y89A-M117L- M216L, D127P-M211 L-P212D-A29G-Y89A-M117V-M216A, D127P-M211 L-P212D-A29G-Y89A- M117V-M216F, D127P-M211 L-P212D-A29G-Y89A-M117V-M216L, D127P-M211 L-P212D-D58P, D127P-M211 L-P212D-D58P-Y89A, D127P-M211 L-P212D-D58P-M117A, D127P-M211 L-P212D-D58P-M117F, D127P-M211 L-P212D-D58P-M117I, D127P-M211 L-P212D-D58P-M117L, D127P- M211 L-P212D-D58P-M117V, D127P-M211 L-P212D-D58P-M216A, D127P-M211 L-P212D-D58P-M216F, D127P-M211 L-P212D-D58P-M216L, D127P-M211 L-P212D-D58P-Y89A-M117A, D127P- M211 L-P212D-D58P-Y89A-M117F, D127P-M211 L-P212D-D58P-Y89A-M117I, D127P-M211 L- P212D-D58P-Y89A-M117L, D127P-M211 L-P212D-D58P-Y89A-M117V, D127P-M211 L-P212D-D58P-Y89A-M216A, D127P-M211 L-P212D-D58P-Y89A-M216F, D127P-M211 L-P212D-D58P-Y89A-M216L, D127P-M211 L-P212D-D58P-M117A-M216A, D127P-M211 L-P212D-D58P-M117A-M216F, D127P-M211 L-P212D-D58P-M117A-M216L, D127P-M211 L-P212D-D58P-M117F-M216A, D127P-M211 L- P212D-D58P-M117F-M216F, D127P-M211 L-P212D-D58P-M117F-M216L, D127P-M211 L-P212D- D58P-M117I-M216A, D127P-M211 L-P212D-D58P-M117I-M216F, D127P-M211 L-P212D-D58P- M117I-M216L, D127P-M211 L-P212D-D58P-M117L-M216A, D127P-M211 L-P212D-D58P-M117L- M216F, D127P-M211 L-P212D-D58P-M117L-M216L, D127P-M211 L-P212D-D58P-M117V-M216A, D127P-M211 L-P212D-D58P-M117V-M216F, D127P-M211 L-P212D-D58P-M117V-M216L, D127P-M211 L-P212D-Y89A, D127P-M211 L-P212D-Y89A-M117A, D127P-M211 L-P212D-Y89A-M117F, D127P-M211 L-P212D-Y89A-M1171, D127P-M211 L-P212D-Y89A-M117L, D127P-M211 L-P212D-Y89A-M117V, D127P-M211 L-P212D-Y89A-M216A, D127P-M211 L-P212D-Y89A-M216F, D127P-M211 L-P212D-Y89A-M216L, D127P-M211 L-P212D-Y89A-M117A-M216A, D127P-M211 L-P212D- Y89A-M117A-M216F, D127P-M211 L-P212D-Y89A-M117A-M216L, D127P-M211 L-P212D-Y89A- M117F-M216A, D127P-M211 L-P212D-Y89A-M117F-M216F, D127P-M211 L-P212D-Y89A-M117F-M216L, D127P-M211 L-P212D-Y89A-M117I-M216A, D127P-M211 L-P212D-Y89A-M117I-M216F, D127P-M211 L-P212D-Y89A-M117I-M216L, D127P-M211 L-P212D-Y89A-M117L-M216A, D127P-M211 L-P212D-Y89A-M117L-M216F, D127P-M211 L-P212D-Y89A-M117L-M216L, D127P-M211 L- P212D-Y89A-M117V-M216A, D127P-M211 L-P212D-Y89A-M117V-M216F, D127P-M211 L-P212D- Y89A-M117V-M216L, D127P-M211 L-P212D-M117A, D127P-M211 L-P212D-M117F, D127P-M211 L-P212D-M117I, D127P-M211 L-P212D-M117L, D127P-M211 L-P212D-M117V, D127P-M211L-P212D-M117A-M216A, D127P-M211 L-P212D-M117A-M216F, D127P-M211 L-P212D-M117A-M216L, D127P-M211 L-P212D-M117F-M216A, D127P-M211 L-P212D-M117F-M216F, D127P-M211 L-P212D-M117F-M216L, D127P-M211 L-P212D-M117I-M216A, D127P-M211 L-P212D-M117I-M216F, D127P-M211 L- P212D-M117I-M216L, D127P-M211 L-P212D-M117L-M216A, D127P-M211 L-P212D-M117L-M216F, D127P-M211 L-P212D-M117L-M216L, D127P-M211 L-P212D-M117V-M216A, D127P-M211 L-P212D-M117V-M216F, D127P-M211 L-P212D-M117V-M216L, D127P-M211 L-P212D-M216A, D127P-M211 L- P212D-M216F, D127P-M211 L-P212D-M216L, P212H-A29G, P212H-A29G-D58P, P212H-A29G-Y89A, P212H-A29G-M117A, P212H-A29G-M117F, P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H-A29G-M216F, P212H-A29G-M216L, P212H-A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H-A29G-D58P-M117F, P212H-A29G-D58P-M117I, P212H-A29G-D58P-M117L, P212H-A29G-D58P-M117V, P212H-A29G-D58P-M216A, P212H-A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A-M117F, P212H-A29G-Y89A-M1171, P212H-A29G-Y89A-M117L, P212H-A29G-Y89A-M117V, P212H-A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A- M216A, P212H-A29G-M117A-M216F, P212H-A29G-M117A-M216L, P212H-A29G-D58P-Y89A- M117A, P212H-A29G-D58P-Y89A-M117F, P212H-A29G-D58P-Y89A-M117I, P212H-A29G-D58P-Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G- D58P-Y89A-M216F, P212H-A29G-D58P-Y89A-M216L, P212H-A29G-Y89A-M117A-M216A, P212H- A29G-Y89A-M117A-M216F, P212H-A29G-Y89A-M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H-A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M1171- M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A-M117L-M216A, P212H-A29G-Y89A-M117L-M216F, P212H-A29G-Y89A-M117L-M216L, P212H-A29G-Y89A-M117V-M216A, P212H-A29G-Y89A-M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P-M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H-D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M117I, P212H-D58P-Y89A-M117L, P212H-D58P-Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P-Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A-M216F, P212H-D58P-M117A-M216L, P212H-D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P-M117I-M216A, P212H-D58P-M117I-M216F, P212H-D58P-M117I-M216L, P212H-D58P-M117L-M216A, P212H-D58P-M117L-M216F, P212H-D58P-M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V-M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H-Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A-M216A, P212H-Y89A-M216F, P212H-Y89A-M216L, P212H-Y89A-M117A-M216A, P212H-Y89A-M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F-M216F, P212H-Y89A-M117F-M216L, P212H-Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L-M216A, P212H-Y89A-M117L-M216F, P212H-Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A-M117V-M216L, P212H-M117A, P212H-M117F, P212H- M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H-M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I-M216A, P212H-M117I-M216F, P212H-M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V-M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H-M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S- A29G-D58P, Q12L-M122L-A222S-A29G-Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L- A222S-A29G-M117F, Q12L-M122L-A222S-A29G-M1171, Q12L-M122L-A222S-A29G-M117L, Q12L-M122L-A222S-A29G-M117V, Q12L-M122L-A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S- A29G-D58P-M117A, Q12L-M122L-A222S-A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P-M117I, Q12L-M122L-A222S-A29G-D58P-M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L- M122L-A222S-A29G-D58P-M216A, Q12L-M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S- A29G-D58P-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A-M117F, Q12L-M122L-A222S-A29G-Y89A-M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L- M122L-A222S-A29G-Y89A-M117V, Q12L-M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S- A29G-Y89A-M216F, Q12L-M122L-A222S-A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A-M216A, Q12L-M122L-A222S-A29G-M117A-M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M117I , Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S- D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L- A222S-D58P-M1171, Q12L-M122L-A222S-D58P-M117L, Q12L-M122L-A222S-D58P-M117V, Q12L-M122L-A222S-D58P-M216A, Q12L-M122L-A222S-D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L-M122L-A222S-D58P-Y89A-M117F, Q12L-M122L- A222S-D58P-Y89A-M1171, Q12L-M122L-A222S-D58P-Y89A-M117L, Q12L-M122L-A222S-D58P-Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A-M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L-M122L-A222S-D58P-M117A-M216A, Q12L-M122L- A222S-D58P-M117A-M216F, Q12L-M122L-A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P-M117F-M216A, Q12L-M122L-A222S-D58P-M117F-M216F, Q12L-M122L-A222S-D58P-M117F-M216L, Q12L-M122L-A222S-D58P-M117I-M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L- M122L-A222S-D58P-M117I-M216L, Q12L-M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S-D58P-M117L-M216F, Q12L-M122L-A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V- M216A, Q12L-M122L-A222S-D58P-M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L-A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L-M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A-M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S-Y89A-M216L, Q12L-M122L-A222S-Y89A-M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A-M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L- A222S-Y89A-M117F-M216F, Q12L-M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A-M117I-M216A, Q12L-M122L-A222S-Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L-M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L- A222S-Y89A-M117L-M216L, Q12L-M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A-M117V-M216F, Q12L-M122L-A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L-M122L-A222S-M117F, Q12L-M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L-A222S-M117V, Q12L-M122L-A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L-M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F- M216F, Q12L-M122L-A222S-M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L- A222S-M117I-M216F, Q12L-M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L-M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S-M117V-M216A, Q12L-M122L-A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L-M122L-A222S-M216A, Q12L-M122L-A222S-M216F, Q12L-M122L-A222S-M216L, wherein the numbering is based in each case on the numbering according to SEQ ID NO:1 and wherein the protease does not comprise any further changes besides the amino acid substitutions mentioned.

In bevorzugten Ausführungsformen umfasst die erfindungsgemäße Protease eine Aminosäuresubstitutionskombination, die aus der aus M211 L-P212D-A29G, M211 L-P212D-A29G- D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L- P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G-M216L, M211 L-P212D- A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G-D58P-M117F, M211 L- P212D-A29G-D58P-M1171, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P- M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D- A29G-Y89A-M1171, M211 L-P212D-A29G-Y89A-M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L- P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G- M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A-M117I , M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D- A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P- Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A-M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L- P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D- A29G-Y89A-M117F-M216L, M211 L-P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A- M117I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L- P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M211 L-P212D- A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P- M117A, M211 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L- P212D-D58P-M216L, M211 L-P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M117I, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A- M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D- D58P-Y89A-M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P- M117F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L- P212D-D58P-M117I-M216F, M211 L-P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L- M216A, M211 L-P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D- D58P-M117V-M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D-Y89A-M117A, M211 L-P212D-Y89A-M117F, M211 L-P212D- Y89A-M117I, M211 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A- M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A- M216A, M211 L-P212D-Y89A-M117A-M216F, M211 L-P212D-Y89A-M117A-M216L, M211L-P212D- Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A- M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L- P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V- M216F, M211 L-P212D-Y89A-M117V-M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L- P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L- P212D-M117A-M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D- M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D-M117I-M216A, M211L-P212D-M1171- M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L- P212D-M117V-M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L bestehenden Gruppe ausgewählt ist, wobei die Nummerierung jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 ist und wobei die Protease neben den genannten Aminosäuresubstitutionen keine weiteren Änderungen umfasst. In preferred embodiments, the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L- P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M1171, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P- M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D- A29G-Y89A-M1171, M211 L-P212D-A29G-Y89A-M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L- P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G- M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A-M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D- A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P- Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A-M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L- P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D- A29G-Y89A-M117F-M216L, M211 L-P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A- M117I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L- P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M211 L-P212D- A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L- P212D-D58P-M216L, M211 L-P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M117I, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A- M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D- D58P-Y89A-M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P- M117F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L- P212D-D58P-M117I-M216F, M211 L-P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L- M216A, M211 L-P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D- D58P-M117V-M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D-Y89A-M117A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M117I, M211 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A- M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A- M216A, M211 L-P212D-Y89A-M117A-M216F, M211 L-P212D-Y89A-M117A-M216L, M211L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A- M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V-M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L- P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L- P212D-M117A-M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D-M117I-M216A, M211L-P212D-M1171- M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L- P212D-M117V-M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO:1 and wherein the protease comprises no further changes besides the amino acid substitutions mentioned.

In bevorzugten Ausführungsformen umfasst die erfindungsgemäße Protease eine Aminosäuresubstitutionskombination, die aus der aus M117A-M211 L-P212D, Y89A-M117A-M211 L- P212D, M117V-M211 L-P212D, A29G-M117V-M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L- P212D, M117L-M211 L-P212D, M211 L-P212D-M216F, D58P-M211 L-P212D-M216A und M211 L- P212D-M216L bestehenden Gruppe ausgewählt ist, wobei die Nummerierung jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 ist und wobei die Protease neben den genannten Aminosäuresubstitutionen keine weiteren Änderungen umfasst. In bevorzugten Ausführungsformen führen die hierin beschriebenen Kombinationen der erfindungsgemäßen Aminosäuresubstitutionen aus Gruppe (i) und (ii) zu einer verbesserten Reinigungsleistung dieser veränderten Protease in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, an mindestens einer proteasesensitiven Anschmutzung. Erfindungsgemäße Proteasen ermöglichen folglich eine verbesserte Entfernung von mindestens einer, bevorzugt mehreren, proteasesensitiven Anschmutzungen auf Textilien und/oder harten Oberflächen, insbesondere Geschirr. Typische proteasesensitive Anschmutzungen umfassen z.B. ei(gelb)-, blut-, milch- und andere proteinhaltige Anschmutzungen. Eine erfindungsgemäße Verbesserung der Reinigungsleistung, insbesondere der proteolytischen Reinigungsleistung, liegt dann vor, wenn die Protease an mindestens einer proteasesensitiven Anschmutzung, die vorzugsweise aus der aus blut-, ei(gelb)-, milch- und anderen proteinhaltigen Anschmutzungen bestehenden Gruppe ausgewählt ist, eine verbesserte Reinigungsleistung gegenüber einer Referenzprotease zeigt. In preferred embodiments, the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V-M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D-M216F, D58P-M211 L-P212D-M216A and M211 L-P212D-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO:1 and wherein the Protease does not contain any further changes besides the amino acid substitutions mentioned. In preferred embodiments, the combinations of the amino acid substitutions according to the invention from groups (i) and (ii) described herein lead to improved cleaning performance of this modified protease in washing or cleaning agents, in particular bleach-containing washing and cleaning agents, preferably automatic dishwashing agents, particularly preferably bleach-containing automatic dishwashing agents, on at least one protease-sensitive soil. Proteases according to the invention therefore enable improved removal of at least one, preferably several, protease-sensitive soils on textiles and/or hard surfaces, in particular dishes. Typical protease-sensitive soils include, for example, egg (yolk), blood, milk, and other protein-containing soils. An improvement in cleaning performance according to the invention, in particular in proteolytic cleaning performance, is present when the protease shows improved cleaning performance compared to a reference protease on at least one protease-sensitive soil, which is preferably selected from the group consisting of blood, egg (yolk), milk and other protein-containing soils.

In bevorzugten Ausführungsformen führen die hierin beschriebenen Kombinationen der erfindungsgemäßen Aminosäuresubstitutionen aus Gruppe (i) und (ii) zu einer verbesserten Stabilität dieser veränderten Protease in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln. In bevorzugten Ausführungsformen führen die hierin beschriebenen Kombinationen der erfindungsgemäßen Aminosäuresubstitutionen aus Gruppe (i) und (ii) zu einer verbesserten Stabilität dieser veränderten Protease in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln. In preferred embodiments, the combinations of the amino acid substitutions from groups (i) and (ii) described herein lead to improved stability of this modified protease in washing or cleaning agents, in particular bleach-containing washing or cleaning agents, preferably automatic dishwashing agents, particularly preferably bleach-containing automatic dishwashing agents. In preferred embodiments, the combinations of the amino acid substitutions from groups (i) and (ii) described herein lead to improved stability of this modified protease in the presence of bleaching agents, in particular oxidizing agents.

Erfindungsgemäße Proteasen können daher in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, eingesetzt werden. Erfindungsgemäße Proteasen können daher in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, eingesetzt werden und in solchen Mitteln eine Reinigungsleistung entfalten. Insbesondere können erfindungsgemäße Proteasen die Reinigungsleistung von bleichmittel- und enzymhaltigen, insbesondere proteasehaltigen, Wasch- und Reinigungsmitteln, insbesondere Maschinengeschirrspülmitteln, verbessern, insbesondere im Hinblick auf proteasesensitive Anschmutzungen. Proteases according to the invention can therefore be used in washing or cleaning agents, in particular bleach-containing washing and cleaning agents, preferably automatic dishwashing agents, particularly preferably bleach-containing automatic dishwashing agents. Proteases according to the invention can therefore be used in washing or cleaning agents, in particular bleach-containing washing and cleaning agents, preferably automatic dishwashing agents, particularly preferably bleach-containing automatic dishwashing agents, and exhibit a cleaning performance in such agents. In particular, proteases according to the invention can improve the cleaning performance of bleach- and enzyme-containing, in particular protease-containing, washing and cleaning agents, in particular automatic dishwashing agents, particularly with regard to protease-sensitive soils.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one Amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably bleach-containing dishwasher detergents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens zwei der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino acid substitutions selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 211 und 212 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus M211 N, M211 L, P212D und P212H, vorzugsweise M211 L und/oder P212D, bestehenden Gruppe ausgewählt ist/sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N, M211L, P212D and P212H, preferably M211L and/or P212D, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably dishwasher detergents, particularly preferably bleach-containing dishwasher detergents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, zwei Aminosäuresubstitutionen, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, two amino acid substitutions selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in washing or cleaning agents, in particular bleach-containing Detergents and cleaning agents, preferably dishwasher detergents, particularly preferably dishwasher detergents containing bleach, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, die Aminosäuresubstitutionen M211 L und P212D, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably dishwasher detergents, particularly preferably bleach-containing dishwasher detergents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus 143V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H und Q12L-M122L-A222S bestehenden Gruppe ausgewählt ist, und (ii) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus A29G, A29G-D58P, A29G-Y89A, A29G-M117A, A29G-M117F, A29G-M1171, A29G- M117L, A29G-M117V, A29G-M216A, A29G-M216F, A29G-M216L, A29G-D58P-Y89A, A29G-D58P- M117A, A29G-D58P-M117F, A29G-D58P-M1171, A29G-D58P-M117L, A29G-D58P-M117V, A29G- D58P-M216A, A29G-D58P-M216F, A29G-D58P-M216L, A29G-Y89A-M117A, A29G-Y89A-M117F, A29G-Y89A-M1171, A29G-Y89A-M117L, A29G-Y89A-M117V, A29G-Y89A-M216A, A29G-Y89A- M216F, A29G-Y89A-M216L, A29G-M117A-M216A, A29G-M117A-M216F, A29G-M117A-M216L, A29G-D58P-Y89A-M117A, A29G-D58P-Y89A-M117F, A29G-D58P-Y89A-M1171, A29G-D58P-Y89A- M117L, A29G-D58P-Y89A-M117V, A29G-D58P-Y89A-M216A, A29G-D58P-Y89A-M216F, A29G- D58P-Y89A-M216L, A29G-Y89A-M117A-M216A, A29G-Y89A-M117A-M216F, A29G-Y89A-M117A- M216L, A29G-Y89A-M117F-M216A, A29G-Y89A-M117F-M216F, A29G-Y89A-M117F-M216L, A29G- Y89A-M117I-M216A, A29G-Y89A-M117I-M216F, A29G-Y89A-M117I-M216L, A29G-Y89A-M117L- M216A, A29G-Y89A-M117L-M216F, A29G-Y89A-M117L-M216L, A29G-Y89A-M117V-M216A, A29G- Y89A-M117V-M216F, A29G-Y89A-M117V-M216L, D58P, D58P-Y89A, D58P-M117A, D58P-M117F, D58P-M117I, D58P-M117L, D58P-M117V, D58P-M216A, D58P-M216F, D58P-M216L, D58P-Y89A- M117A, D58P-Y89A-M117F, D58P-Y89A-M1171, D58P-Y89A-M117L, D58P-Y89A-M117V, D58P- Y89A-M216A, D58P-Y89A-M216F, D58P-Y89A-M216L, D58P-M117A-M216A, D58P-M117A-M216F, D58P-M117A-M216L, D58P-M117F-M216A, D58P-M117F-M216F, D58P-M117F-M216L, D58P- M117I-M216A, D58P-M117I-M216F, D58P-M117I-M216L, D58P-M117L-M216A, D58P-M117L- M216F, D58P-M117L-M216L, D58P-M117V-M216A, D58P-M117V-M216F, D58P-M117V-M216L, Y89A, Y89A-M117A, Y89A-M117F, Y89A-M1171, Y89A-M117L, Y89A-M117V, Y89A-M216A, Y89A- M216F, Y89A-M216L, Y89A-M117A-M216A, Y89A-M117A-M216F, Y89A-M117A-M216L, Y89A- M117F-M216A, Y89A-M117F-M216F, Y89A-M117F-M216L, Y89A-M117I-M216A, Y89A-M117I- M216F, Y89A-M117I-M216L, Y89A-M117L-M216A, Y89A-M117L-M216F, Y89A-M117L-M216L, Y89A-M117V-M216A, Y89A-M117V-M216F, Y89A-M117V-M216L, M117A, M117F, M117I, M117L, M117V, M117A-M216A, M117A-M216F, M117A-M216L, M117F-M216A, M117F-M216F, M117F- M216L, M117I-M216A, M117I-M216F, M117I-M216L, M117L-M216A, M117L-M216F, M117L-M216L, M117V-M216A, M117V-M216F, M117V-M216L, M216A, M216F, M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case with reference to the numbering according to SEQ ID NO:1, (i) an amino acid substitution or Amino acid substitution combination selected from the group consisting of 143V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H and Q12L-M122L-A222S, and (ii) an amino acid substitution or amino acid substitution combination selected from the group consisting of A29G, A29G-D58P, A29G-Y89A, A29G-M117A, A29G-M117F, A29G-M1171, A29G-M117L, A29G-M117V, A29G-M216A, A29G-M216F, A29G-M216L, A29G-D58P-Y89A, A29G-D58P-M117A, A29G-D58P-M117F, A29G-D58P-M1171, A29G-D58P-M117L, A29G-D58P-M117V, A29G- D58P-M216A, A29G-D58P-M216F, A29G-D58P-M216L, A29G-Y89A-M117A, A29G-Y89A-M117F, A29G-Y89A-M1171, A29G-Y89A-M117L, A29G-Y89A-M117V, A29G-Y89A-M216A, A29G-Y89A-M216F, A29G-Y89A-M216L, A29G-M117A-M216A, A29G-M117A-M216F, A29G-M117A-M216L, A29G-D58P-Y89A-M117A, A29G-D58P-Y89A-M117F, A29G-D58P-Y89A-M1171, A29G-D58P-Y89A-M117L, A29G-D58P-Y89A-M117V, A29G-D58P-Y89A-M216A, A29G-D58P-Y89A-M216F, A29G-D58P-Y89A-M216L, A29G-Y89A-M117A-M216A, A29G-Y89A-M117A-M216F, A29G-Y89A-M117A-M216L, A29G-Y89A-M117F-M216A, A29G-Y89A-M117F-M216F, A29G-Y89A-M117F-M216L, A29G-Y89A-M117I-M216A, A29G-Y89A-M117I-M216F, A29G-Y89A-M117I-M216L, A29G-Y89A-M117L-M216A, A29G-Y89A-M117L-M216F, A29G-Y89A-M117L-M216L, A29G-Y89A-M117V-M216A, A29G-Y89A-M117V-M216F, A29G-Y89A-M117V-M216L, D58P, D58P-Y89A, D58P-M117A, D58P-M117F, D58P-M117I, D58P-M117L, D58P-M117V, D58P-M216A, D58P-M216F, D58P-M216L, D58P-Y89A-M117A, D58P-Y89A-M117F, D58P-Y89A-M1171, D58P-Y89A-M117L, D58P-Y89A-M117V, D58P-Y89A-M216A, D58P-Y89A-M216F, D58P-Y89A-M216L, D58P-M117A-M216A, D58P-M117A-M216F, D58P-M117A-M216L, D58P-M117F-M216A, D58P-M117F-M216F, D58P-M117F-M216L, D58P-M117I-M216A, D58P-M117I-M216F, D58P-M117I-M216L, D58P-M117L-M216A, D58P-M117L-M216F, D58P-M117L-M216L, D58P-M117V-M216A, D58P-M117V-M216F, D58P-M117V-M216L, Y89A, Y89A-M117A, Y89A-M117F, Y89A-M1171, Y89A-M117L, Y89A-M117V, Y89A-M216A, Y89A-M216F, Y89A-M216L, Y89A-M117A-M216A, Y89A-M117A-M216F, Y89A-M117A-M216L, Y89A-M117F-M216A, Y89A-M117F-M216F, Y89A-M117F-M216L, Y89A-M117I-M216A, Y89A-M117I-M216F, Y89A-M117I-M216L, Y89A-M117L-M216A, Y89A-M117L-M216F, Y89A-M117L-M216L, Y89A-M117V-M216A, Y89A-M117V-M216F, Y89A-M117V-M216L, M117A, M117F, M117I, M117L, M117V, M117A-M216A, M117A-M216F, M117A-M216L, M117F-M216A, M117F-M216F, M117F-M216L, M117I-M216A, M117I-M216F, M117I-M216L, M117L-M216A, M117L-M216F, M117L-M216L, M117V-M216A, M117V-M216F, M117V-M216L, M216A, M216F, M216L, wherein the protease has improved stability in washing or cleaning agents, in particular bleach-containing washing and cleaning agents, preferably automatic dishwashing detergents, in particular preferably bleach-containing dishwasher detergents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) eine Aminosäuresubstitution bzw. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% is identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or

Aminosäuresubstitutionskombination, die aus der aus I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H und Q12L-M122L-A222S bestehenden Gruppe ausgewählt ist, und (ii) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus M117A, M117A-Y89L, M117V, M117V-A29G, M117F, M117I, M117L, M216F, D58P- M216A, M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. Amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H and Q12L-M122L-A222S, and (ii) an amino acid substitution or amino acid substitution combination selected from the group consisting of M117A, M117A-Y89L, M117V, M117V-A29G, M117F, M117I, M117L, M216F, D58P-M216A, M216L, wherein the protease has improved stability in washing or cleaning agents, in particular bleach-containing washing and cleaning agents, preferably Dishwashing detergents, particularly preferably dishwashing detergents containing bleach, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , eine Aminosäuresubstitutionskombination aufweist, die aus der aus I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M117I, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P- M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P-M216L, I43V-A29G-Y89A-M117A, I43V-A29G- Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G-Y89A-M117L, I43V-A29G-Y89A-M117V, I43V- A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V-A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A-M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G- D58P-Y89A-M117F, I43V-A29G-D58P-Y89A-M1171, I43V-A29G-D58P-Y89A-M117L, I43V-A29G- D58P-Y89A-M117V, I43V-A29G-D58P-Y89A-M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G- D58P-Y89A-M216L, I43V-A29G-Y89A-M117A-M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G- Y89A-M117A-M216L, I43V-A29G-Y89A-M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V- A29G-Y89A-M117F-M216L, I43V-A29G-Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V- A29G-Y89A-M117I-M216L, I43V-A29G-Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V- A29G-Y89A-M117L-M216L, I43V-A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P- M117F, I43V-D58P-M1171, I43V-D58P-M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P- M216F, I43V-D58P-M216L, I43V-D58P-Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A- M117I, I43V-D58P-Y89A-M117L, I43V-D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P- Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V- D58P-M117A-M216L, I43V-D58P-M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F- M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P- M117L-M216A, I43V-D58P-M117L-M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V-D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A- M117F, I43V-Y89A-M117I, I43V-Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A- M216F, I43V-Y89A-M216L, I43V-Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A- M117A-M216L, I43V-Y89A-M117F-M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V-Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L- M216A, I43V-Y89A-M117L-M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V- Y89A-M117V-M216F, I43V-Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V- M117L, I43V-M117V, I43V-M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F- M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V- M117I-M216L, I43V-M117L-M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V-M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S- T156A-A29G, M122L-N154S-T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S- T156A-A29G-M117A, M122L-N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M1171, M122L-N154S-T156A-A29G-M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A- A29G-M216A, M122L-N154S-T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L- N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A- A29G-D58P-M117F, M122L-N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P- M117L, M122L-N154S-T156A-A29G-D58P-M117V, M122L-N154S-T156A-A29G-D58P-M216A, M122L-N154S-T156A-A29G-D58P-M216F, M122L-N154S-T156A-A29G-D58P-M216L, M122L- N154S-T156A-A29G-Y89A-M117A, M122L-N154S-T156A-A29G-Y89A-M117F, M122L-N154S- T156A-A29G-Y89A-M117I, M122L-N154S-T156A-A29G-Y89A-M117L, M122L-N154S-T156A-A29G- Y89A-M117V, M122L-N154S-T156A-A29G-Y89A-M216A, M122L-N154S-T156A-A29G-Y89A-M216F, M122L-N154S-T156A-A29G-Y89A-M216L, M122L-N154S-T156A-A29G-M117A-M216A, M122L- N154S-T156A-A29G-M117A-M216F, M122L-N154S-T156A-A29G-M117A-M216L, M122L-N154S- T156A-A29G-D58P-Y89A-M117A, M122L-N154S-T156A-A29G-D58P-Y89A-M117F, M122L-N154S- T156A-A29G-D58P-Y89A-M1171, M122L-N154S-T156A-A29G-D58P-Y89A-M117L, M122L-N154S- T156A-A29G-D58P-Y89A-M117V, M122L-N154S-T156A-A29G-D58P-Y89A-M216A, M122L-N154S- T156A-A29G-D58P-Y89A-M216F, M122L-N154S-T156A-A29G-D58P-Y89A-M216L, M122L-N154S- T156A-A29G-Y89A-M117A-M216A, M122L-N154S-T156A-A29G-Y89A-M117A-M216F, M122L- N154S-T156A-A29G-Y89A-M117A-M216L, M122L-N154S-T156A-A29G-Y89A-M117F-M216A, M122L-N154S-T156A-A29G-Y89A-M117F-M216F, M122L-N154S-T156A-A29G-Y89A-M117F- M216L, M122L-N154S-T156A-A29G-Y89A-M117I-M216A, M122L-N154S-T156A-A29G-Y89A-M1171- M216F, M122L-N154S-T156A-A29G-Y89A-M117I-M216L, M122L-N154S-T156A-A29G-Y89A-M117L- M216A, M122L-N154S-T156A-A29G-Y89A-M117L-M216F, M122L-N154S-T156A-A29G-Y89A- M117L-M216L, M122L-N154S-T156A-A29G-Y89A-M117V-M216A, M122L-N154S-T156A-A29G- Y89A-M117V-M216F, M122L-N154S-T156A-A29G-Y89A-M117V-M216L, M122L-N154S-T156A- D58P, M122L-N154S-T156A-D58P-Y89A, M122L-N154S-T156A-D58P-M117A, M122L-N154S- T156A-D58P-M117F, M122L-N154S-T156A-D58P-M1171, M122L-N154S-T156A-D58P-M117L, M122L-N154S-T156A-D58P-M117V, M122L-N154S-T156A-D58P-M216A, M122L-N154S-T156A- D58P-M216F, M122L-N154S-T156A-D58P-M216L, M122L-N154S-T156A-D58P-Y89A-M117A, M122L-N154S-T156A-D58P-Y89A-M117F, M122L-N154S-T156A-D58P-Y89A-M117I, M122L-N154S- T156A-D58P-Y89A-M117L, M122L-N154S-T156A-D58P-Y89A-M117V, M122L-N154S-T156A-D58P- Y89A-M216A, M122L-N154S-T156A-D58P-Y89A-M216F, M122L-N154S-T156A-D58P-Y89A-M216L, M122L-N154S-T156A-D58P-M117A-M216A, M122L-N154S-T156A-D58P-M117A-M216F, M122L- N154S-T156A-D58P-M117A-M216L, M122L-N154S-T156A-D58P-M117F-M216A, M122L-N154S- T156A-D58P-M117F-M216F, M122L-N154S-T156A-D58P-M117F-M216L, M122L-N154S-T156A- D58P-M117I-M216A, M122L-N154S-T156A-D58P-M117I-M216F, M122L-N154S-T156A-D58P- M117I-M216L, M122L-N154S-T156A-D58P-M117L-M216A, M122L-N154S-T156A-D58P-M117L- M216F, M122L-N154S-T156A-D58P-M117L-M216L, M122L-N154S-T156A-D58P-M117V-M216A, M122L-N154S-T156A-D58P-M117V-M216F, M122L-N154S-T156A-D58P-M117V-M216L, M122L- N154S-T156A-Y89A, M122L-N154S-T156A-Y89A-M117A, M122L-N154S-T156A-Y89A-M117F, M122L-N154S-T156A-Y89A-M117I, M122L-N154S-T156A-Y89A-M117L, M122L-N154S-T156A- Y89A-M117V, M122L-N154S-T156A-Y89A-M216A, M122L-N154S-T156A-Y89A-M216F, M122L- N154S-T156A-Y89A-M216L, M122L-N154S-T156A-Y89A-M117A-M216A, M122L-N154S-T156A- Y89A-M117A-M216F, M122L-N154S-T156A-Y89A-M117A-M216L, M122L-N154S-T156A-Y89A- M117F-M216A, M122L-N154S-T156A-Y89A-M117F-M216F, M122L-N154S-T156A-Y89A-M117F- M216L, M122L-N154S-T156A-Y89A-M117I-M216A, M122L-N154S-T156A-Y89A-M117I-M216F, M122L-N154S-T156A-Y89A-M117I-M216L, M122L-N154S-T156A-Y89A-M117L-M216A, M122L- N154S-T156A-Y89A-M117L-M216F, M122L-N154S-T156A-Y89A-M117L-M216L, M122L-N154S- T156A-Y89A-M117V-M216A, M122L-N154S-T156A-Y89A-M117V-M216F, M122L-N154S-T156A- Y89A-M117V-M216L, M122L-N154S-T156A-M117A, M122L-N154S-T156A-M117F, M122L-N154S- T156A-M117I, M122L-N154S-T156A-M117L, M122L-N154S-T156A-M117V, M122L-N154S-T156A- M117A-M216A, M122L-N154S-T156A-M117A-M216F, M122L-N154S-T156A-M117A-M216L, M122L- N154S-T156A-M117F-M216A, M122L-N154S-T156A-M117F-M216F, M122L-N154S-T156A-M117F- M216L, M122L-N154S-T156A-M117I-M216A, M122L-N154S-T156A-M117I-M216F, M122L-N154S- T156A-M117I-M216L, M122L-N154S-T156A-M117L-M216A, M122L-N154S-T156A-M117L-M216F, M122L-N154S-T156A-M117L-M216L, M122L-N154S-T156A-M117V-M216A, M122L-N154S-T156A- M117V-M216F, M122L-N154S-T156A-M117V-M216L, M122L-N154S-T156A-M216A, M122L-N154S- T156A-M216F, M122L-N154S-T156A-M216L, M211 N-P212D-A29G, M211 N-P212D-A29G-D58P, M211 N-P212D-A29G-Y89A, M211 N-P212D-A29G-M117A, M211 N-P212D-A29G-M117F, M211 N- P212D-A29G-M1171, M211 N-P212D-A29G-M117L, M211 N-P212D-A29G-M117V, M211 N-P212D- A29G-M216A, M211 N-P212D-A29G-M216F, M211 N-P212D-A29G-M216L, M211 N-P212D-A29G- D58P-Y89A, M211 N-P212D-A29G-D58P-M117A, M211 N-P212D-A29G-D58P-M117F, M211 N- P212D-A29G-D58P-M1171, M211 N-P212D-A29G-D58P-M117L, M211 N-P212D-A29G-D58P-M117V, M211 N-P212D-A29G-D58P-M216A, M211 N-P212D-A29G-D58P-M216F, M211 N-P212D-A29G- D58P-M216L, M211 N-P212D-A29G-Y89A-M117A, M211 N-P212D-A29G-Y89A-M117F, M211 N- P212D-A29G-Y89A-M117I, M211 N-P212D-A29G-Y89A-M117L, M211 N-P212D-A29G-Y89A-M117V, M211 N-P212D-A29G-Y89A-M216A, M211 N-P212D-A29G-Y89A-M216F, M211 N-P212D-A29G-Y89A- M216L, M211 N-P212D-A29G-M117A-M216A, M211 N-P212D-A29G-M117A-M216F, M211 N-P212D- A29G-M117A-M216L, M211 N-P212D-A29G-D58P-Y89A-M117A, M211 N-P212D-A29G-D58P-Y89A- M117F, M211 N-P212D-A29G-D58P-Y89A-M117I, M211 N-P212D-A29G-D58P-Y89A-M117L, M211 N- P212D-A29G-D58P-Y89A-M117V, M211 N-P212D-A29G-D58P-Y89A-M216A, M211 N-P212D-A29G- D58P-Y89A-M216F, M211 N-P212D-A29G-D58P-Y89A-M216L, M211 N-P212D-A29G-Y89A-M117A- M216A, M211 N-P212D-A29G-Y89A-M117A-M216F, M211 N-P212D-A29G-Y89A-M117A-M216L, M211 N-P212D-A29G-Y89A-M117F-M216A, M211 N-P212D-A29G-Y89A-M117F-M216F, M211 N- P212D-A29G-Y89A-M117F-M216L, M211 N-P212D-A29G-Y89A-M117I-M216A, M211 N-P212D-A29— Y89A-M117I-M216F, M211 N-P212D-A29G-Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L- M216A, M211 N-P212D-A29G-Y89A-M117L-M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 N-P212D-A29G-Y89A-M117V-M216A, M211 N-P212D-A29G-Y89A-M117V-M216F, M211 N- P212D-A29— Y89A-M117V-M216L, M211 N-P212D-D58P, M211 N-P212D-D58P-Y89A, M211 N- P212D-D58P-M117A, M211 N-P212D-D58P-M117F, M211 N-P212D-D58P-M117I, M211 N-P212D- D58P-M117L, M211 N-P212D-D58P-M117V, M211 N-P212D-D58P-M216A, M211 N-P212D-D58P- M216F, M211 N-P212D-D58P-M216L, M211N-P212D-D58P-Y89A-M117A, M211 N-P212D-D58P- Y89A-M117F, M211 N-P212D-D58P-Y89A-M117I, M211 N-P212D-D58P-Y89A-M117L, M211 N- P212D-D58P-Y89A-M117V, M211 N-P212D-D58P-Y89A-M216A, M211 N-P212D-D58P-Y89A-M216F, M211 N-P212D-D58P-Y89A-M216L, M211 N-P212D-D58P-M117A-M216A, M211 N-P212D-D58P- M117A-M216F, M211 N-P212D-D58P-M117A-M216L, M211 N-P212D-D58P-M117F-M216A, M211 N- P212D-D58P-M117F-M216F, M211 N-P212D-D58P-M117F-M216L, M211 N-P212D-D58P-M1171- M216A, M211 N-P212D-D58P-M117I-M216F, M211 N-P212D-D58P-M117I-M216L, M211 N-P212D- D58P-M117L-M216A, M211 N-P212D-D58P-M117L-M216F, M211 N-P212D-D58P-M117L-M216L, M211 N-P212D-D58P-M117V-M216A, M211 N-P212D-D58P-M117V-M216F, M211 N-P212D-D58P- M117V-M216L, M211 N-P212D-Y89A, M211 N-P212D-Y89A-M117A, M211 N-P212D-Y89A-M117F, M211 N-P212D-Y89A-M117I, M211 N-P212D-Y89A-M117L, M211 N-P212D-Y89A-M117V, M211 N- P212D-Y89A-M216A, M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 N-P212D- Y89A-M117A-M216A, M211 N-P212D-Y89A-M117A-M216F, M211 N-P212D-Y89A-M117A-M216L, M211 N-P212D-Y89A-M117F-M216A, M211 N-P212D-Y89A-M117F-M216F, M211 N-P212D-Y89A- M117F-M216L, M211 N-P212D-Y89A-M117I-M216A, M211 N-P212D-Y89A-M117I-M216F, M211 N- P212D-Y89A-M117I-M216L, M211 N-P212D-Y89A-M117L-M216A, M211 N-P212D-Y89A-M117L- M216F, M211 N-P212D-Y89A-M117L-M216L, M211 N-P212D-Y89A-M117V-M216A, M211 N-P212D- Y89A-M117V-M216F, M211 N-P212D-Y89A-M117V-M216L, M211 N-P212D-M117A, M211 N-P212D- M117F, M211 N-P212D-M117I, M211 N-P212D-M117L, M211 N-P212D-M117V, M211 N-P212D- M117A-M216A, M211 N-P212D-M117A-M216F, M211 N-P212D-M117A-M216L, M211 N-P212D- M117F-M216A, M211 N-P212D-M117F-M216F, M211 N-P212D-M117F-M216L, M211 N-P212D-M1171- M216A, M211 N-P212D-M117I-M216F, M211 N-P212D-M117I-M216L, M211 N-P212D-M117L-M216A, M211 N-P212D-M117L-M216F, M211 N-P212D-M117L-M216L, M211 N-P212D-M117V-M216A, M211 N-P212D-M117V-M216F, M211 N-P212D-M117V-M216L, M211 N-P212D-M216A, M211 N- P212D-M216F, M211 N-P212D-M216L, M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L- P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D- A29G-M117I, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G- M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P- Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G- D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D- A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L- P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M1171, M211 L-P212D-A29G-Y89A-M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A- M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D- A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D- A29G-D58P-Y89A-M117I , M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P- Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L- P212D-A29G-Y89A-M117A-M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L-P212D- A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A- M117F-M216L, M211 L-P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L- P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G- Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M211 L-P212D-A29G-Y89A- M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L- P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D- D58P-M216L, M211 L-P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L- P212D-D58P-Y89A-M1171, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A- M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D- D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L-P212D-D58P- M117I-M216F, M211 L-P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L- P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D-D58P-M117V- M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D- Y89A, M211 L-P212D-Y89A-M117A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M117I, M211 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L- P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L- P212D-Y89A-M117A-M216F, M211 L-P212D-Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F- M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D- Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A- M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L- P212D-Y89A-M117V-M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A- M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L- P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D- M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V- M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L, G160S-A29G, G160S- A29G-D58P, G160S-A29G-Y89A, G160S-A29G-M117A, G160S-A29G-M117F, G160S-A29G-M1171, G160S-A29G-M117L, G160S-A29G-M117V, G160S-A29G-M216A, G160S-A29G-M216F, G160S- A29G-M216L, G160S-A29G-D58P-Y89A, G160S-A29G-D58P-M117A, G160S-A29G-D58P-M117F, G160S-A29G-D58P-M1171, G160S-A29G-D58P-M117L, G160S-A29G-D58P-M117V, G160S-A29G- D58P-M216A, G160S-A29G-D58P-M216F, G160S-A29G-D58P-M216L, G160S-A29G-Y89A-M117A, G160S-A29G-Y89A-M117F, G160S-A29G-Y89A-M1171, G160S-A29G-Y89A-M117L, G160S-A29G- Y89A-M117V, G160S-A29G-Y89A-M216A, G160S-A29G-Y89A-M216F, G160S-A29G-Y89A-M216L, G160S-A29G-M117A-M216A, G160S-A29G-M117A-M216F, G160S-A29G-M117A-M216L, G160S- A29G-D58P-Y89A-M117A, G160S-A29G-D58P-Y89A-M117F, G160S-A29G-D58P-Y89A-M117I, G160S-A29G-D58P-Y89A-M117L, G160S-A29G-D58P-Y89A-M117V, G160S-A29G-D58P-Y89A- M216A, G160S-A29G-D58P-Y89A-M216F, G160S-A29G-D58P-Y89A-M216L, G160S-A29G-Y89A- M117A-M216A, G160S-A29G-Y89A-M117A-M216F, G160S-A29G-Y89A-M117A-M216L, G160S- A29G-Y89A-M117F-M216A, G160S-A29G-Y89A-M117F-M216F, G160S-A29G-Y89A-M117F-M216L, G160S-A29G-Y89A-M117I-M216A, G160S-A29G-Y89A-M117I-M216F, G160S-A29G-Y89A-M1171- M216L, G160S-A29G-Y89A-M117L-M216A, G160S-A29G-Y89A-M117L-M216F, G160S-A29G-Y89A- M117L-M216L, G160S-A29G-Y89A-M117V-M216A, G160S-A29G-Y89A-M117V-M216F, G160S- A29G-Y89A-M117V-M216L, G160S-D58P, G160S-D58P-Y89A, G160S-D58P-M117A, G160S-D58P- M117F, G160S-D58P-M1171, G160S-D58P-M117L, G160S-D58P-M117V, G160S-D58P-M216A, G160S-D58P-M216F, G160S-D58P-M216L, G160S-D58P-Y89A-M117A, G160S-D58P-Y89A-M117F, G160S-D58P-Y89A-M1171, G160S-D58P-Y89A-M117L, G160S-D58P-Y89A-M117V, G160S-D58P- Y89A-M216A, G160S-D58P-Y89A-M216F, G160S-D58P-Y89A-M216L, G160S-D58P-M117A-M216A, G160S-D58P-M117A-M216F, G160S-D58P-M117A-M216L, G160S-D58P-M117F-M216A, G160S- D58P-M117F-M216F, G160S-D58P-M117F-M216L, G160S-D58P-M117I-M216A, G160S-D58P- M117I-M216F, G160S-D58P-M117I-M216L, G160S-D58P-M117L-M216A, G160S-D58P-M117L- M216F, G160S-D58P-M117L-M216L, G160S-D58P-M117V-M216A, G160S-D58P-M117V-M216F, G160S-D58P-M117V-M216L, G160S-Y89A, G160S-Y89A-M117A, G160S-Y89A-M117F, G160S- Y89A-M117I, G160S-Y89A-M117L, G160S-Y89A-M117V, G160S-Y89A-M216A, G160S-Y89A- M216F, G160S-Y89A-M216L, G160S-Y89A-M117A-M216A, G160S-Y89A-M117A-M216F, G160S- Y89A-M117A-M216L, G160S-Y89A-M117F-M216A, G160S-Y89A-M117F-M216F, G160S-Y89A- M117F-M216L, G160S-Y89A-M117I-M216A, G160S-Y89A-M117I-M216F, G160S-Y89A-M1171- M216L, G160S-Y89A-M117L-M216A, G160S-Y89A-M117L-M216F, G160S-Y89A-M117L-M216L, G160S-Y89A-M117V-M216A, G160S-Y89A-M117V-M216F, G160S-Y89A-M117V-M216L, G160S- M117A, G160S-M117F, G160S-M117I, G160S-M117L, G160S-M117V, G160S-M117A-M216A, G160S-M117A-M216F, G160S-M117A-M216L, G160S-M117F-M216A, G160S-M117F-M216F, G160S-M117F-M216L, G160S-M117I-M216A, G160S-M117I-M216F, G160S-M117I-M216L, G160S- M117L-M216A, G160S-M117L-M216F, G160S-M117L-M216L, G160S-M117V-M216A, G160S- M117V-M216F, G160S-M117V-M216L, G160S-M216A, G160S-M216F, G160S-M216L, D127P- M211 L-P212D-A29G, D127P-M211 L-P212D-A29G-D58P, D127P-M211 L-P212D-A29G-Y89A, D127P-M211 L-P212D-A29G-M117A, D127P-M211 L-P212D-A29G-M117F, D127P-M211 L-P212D- A29G-M117I, D127P-M211 L-P212D-A29G-M117L, D127P-M211 L-P212D-A29G-M117V, D127P- M211 L-P212D-A29G-M216A, D127P-M211 L-P212D-A29G-M216F, D127P-M211 L-P212D-A29G- M216L, D127P-M211 L-P212D-A29G-D58P-Y89A, D127P-M211 L-P212D-A29G-D58P-M117A, D127P-M211 L-P212D-A29G-D58P-M117F, D127P-M211 L-P212D-A29G-D58P-M1171, D127P- M211 L-P212D-A29G-D58P-M117L, D127P-M211 L-P212D-A29G-D58P-M117V, D127P-M211 L- P212D-A29G-D58P-M216A, D127P-M211 L-P212D-A29G-D58P-M216F, D127P-M211 L-P212D- A29G-D58P-M216L, D127P-M211 L-P212D-A29G-Y89A-M117A, D127P-M211 L-P212D-A29G-Y89A- M117F, D127P-M211 L-P212D-A29G-Y89A-M1171, D127P-M211 L-P212D-A29G-Y89A-M117L, D127P-M211 L-P212D-A29G-Y89A-M117V, D127P-M211 L-P212D-A29G-Y89A-M216A, D127P- M211 L-P212D-A29G-Y89A-M216F, D127P-M211 L-P212D-A29G-Y89A-M216L, D127P-M211 L- P212D-A29G-M117A-M216A, D127P-M211 L-P212D-A29G-M117A-M216F, D127P-M211 L-P212D- A29G-M117A-M216L, D127P-M211 L-P212D-A29G-D58P-Y89A-M117A, D127P-M211 L-P212D- A29G-D58P-Y89A-M117F, D127P-M211 L-P212D-A29G-D58P-Y89A-M1171, D127P-M211 L-P212D- A29G-D58P-Y89A-M117L, D127P-M211 L-P212D-A29G-D58P-Y89A-M117V, D127P-M211 L-P212D- A29G-D58P-Y89A-M216A, D127P-M211 L-P212D-A29G-D58P-Y89A-M216F, D127P-M211 L-P212D- A29G-D58P-Y89A-M216L, D127P-M211 L-P212D-A29G-Y89A-M117A-M216A, D127P-M211 L- P212D-A29G-Y89A-M117A-M216F, D127P-M211 L-P212D-A29G-Y89A-M117A-M216L, D127P- M211 L-P212D-A29G-Y89A-M117F-M216A, D127P-M211 L-P212D-A29G-Y89A-M117F-M216F, D127P-M211 L-P212D-A29G-Y89A-M117F-M216L, D127P-M211 L-P212D-A29G-Y89A-M117I-M216A, D127P-M211 L-P212D-A29— Y89A-M117I-M216F, D127P-M211 L-P212D-A29G-Y89A-M117I-M216L, D127P-M211 L-P212D-A29G-Y89A-M117L-M216A, D127P-M211 L-P212D-A29G-Y89A-M117L- M216F, D127P-M211 L-P212D-A29G-Y89A-M117L-M216L, D127P-M211 L-P212D-A29G-Y89A- M117V-M216A, D127P-M211 L-P212D-A29G-Y89A-M117V-M216F, D127P-M211 L-P212D-A29G- Y89A-M117V-M216L, D127P-M211 L-P212D-D58P, D127P-M211 L-P212D-D58P-Y89A, D127P- M211 L-P212D-D58P-M117A, D127P-M211 L-P212D-D58P-M117F, D127P-M211 L-P212D-D58P- M117I, D127P-M211 L-P212D-D58P-M117L, D127P-M211 L-P212D-D58P-M117V, D127P-M211 L- P212D-D58P-M216A, D127P-M211 L-P212D-D58P-M216F, D127P-M211 L-P212D-D58P-M216L, D127P-M211 L-P212D-D58P-Y89A-M117A, D127P-M211 L-P212D-D58P-Y89A-M117F, D127P-In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M117I, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P-M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P-M216L, I43V-A29G-Y89A-M117A, I43V-A29G-Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G-Y89A-M117L, I43V-A29G-Y89A-M117V, I43V-A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V-A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A-M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G-D58P-Y89A-M117F, I43V-A29G-D58P-Y89A-M1171, I43V-A29G-D58P-Y89A-M117L, I43V-A29G-D58P-Y89A-M117V, I43V-A29G-D58P-Y89A-M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G- D58P-Y89A-M216L, I43V-A29G-Y89A-M117A-M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G- Y89A-M117A-M216L, I43V-A29G-Y89A-M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V-A29G-Y89A-M117F-M216L, I43V-A29G-Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V- A29G-Y89A-M117I-M216L, I43V-A29G-Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V- A29G-Y89A-M117L-M216L, I43V-A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P-M117F, I43V-D58P-M1171, I43V-D58P-M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P-M216F, I43V-D58P-M216L, I43V-D58P-Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A-M117I, I43V-D58P-Y89A-M117L, I43V-D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P- Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V- D58P-M117A-M216L, I43V-D58P-M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F-M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P-M117L-M216A, I43V-D58P-M117L-M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V-D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A- M117F, I43V-Y89A-M117I, I43V-Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A-M216F, I43V-Y89A-M216L, I43V-Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A-M117A-M216L, I43V-Y89A-M117F-M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V-Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L-M216A, I43V-Y89A-M117L-M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V-Y89A-M117V-M216F, I43V-Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V-M117L, I43V-M117V, I43V-M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F-M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V-M117I-M216L, I43V-M117L-M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V-M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, 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N-P212D-D58P-M216F, M211 N-P212D-D58P-M216L, M211N-P212D-D58P-Y89A-M117A, M211 N-P212D-D58P-Y89A-M117F, M211 N-P212D-D58P-Y89A-M117I, M211 N-P212D-D58P-Y89A-M117L, M211 N- P212D-D58P-Y89A-M117V, M211 N-P212D-D58P-Y89A-M216A, M211 N-P212D-D58P-Y89A-M216F, M211 N-P212D-D58P-Y89A-M216L, M211 M211 N-P212D-D58P-M117A-M216A, M211 N- P212D-D58P-M117F-M216F, M211 N-P212D-D58P-M117F-M216L, M211 N-P212D-D58P-M1171- M216A, M211 N-P212D-D58P-M117I-M216F, M211 M211 N-P212D-D58P-M117V-M216A, M211 N-P212D-D58P-M117V-M216F, M211 N-P212D-D58P-M117V-M216L, M211 N-P212D-Y89A, M211 N-P212D-Y89A-M117A, M211 N-P212D-Y89A-M117F, M211 N-P212D-Y89A-M117I, M211 N-P212D-Y89A-M117L, M211 N-P212D-Y89A-M117V, M211 N-P212D-Y89A-M216A, M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 N-P212D-Y89A-M117A-M216A, M211 N-P212D-Y89A-M117A-M216F, M211 N-P212D-Y89A-M117A-M216L, M211 N-P212D-Y89A-M117F-M216A, M211 N-P212D-Y89A-M117F-M216F, M211 N-P212D-Y89A-M117F-M216L, M211 N-P212D-Y89A-M117I-M216A, M211 N-P212D-Y89A-M117I-M216F, M211 N-P212D-Y89A-M117I-M216L, M211 N-P212D-Y89A-M117L-M216A, M211 N-P212D-Y89A-M117L- M216F, M211 M211 N-P212D-Y89A-M117V-M216L, M211 N-P212D-Y89A-M117V-M216L, M211 M211 N-P212D-M117V M211 N-P212D-M117F-M216L M211 N-P212D-M1171- M216A, M211 N-P212D-M117I-M216F, M211 N-P212D-M117I-M216L, M211 N-P212D-M117L-M216A, M211 N-P212D-M117L-M216F, M211 N-P212D-M117L-M216L, M211 N-P212D-M117V-M216A, M211 N-P212D-M117V-M216F, M211 N-P212D-M117V-M216L, M211 N-P212D-M216A, M211 P212D-M216F, M211 N-P212D-M216L, M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D- A29G-M117I, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G- M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G- D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D- 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L-P212D-Y89A-M216F, D127P-M211 L-P212D-Y89A-M216L, D127P-M211 L- P212D-Y89A-M117A-M216A, D127P-M211 L-P212D-Y89A-M117A-M216F, D127P-M211 L-P212D- Y89A-M117A-M216L, D127P-M211 L-P212D-Y89A-M117F-M216A, D127P-M211 L-P212D-Y89A- M117F-M216F, D127P-M211 L-P212D-Y89A-M117F-M216L, D127P-M211 L-P212D-Y89A-M1171- M216A, D127P-M211 L-P212D-Y89A-M117I-M216F, D127P-M211 L-P212D-Y89A-M117I-M216L, D127P-M211 L-P212D-Y89A-M117L-M216A, D127P-M211 L-P212D-Y89A-M117L-M216F, D127P- M211 L-P212D-Y89A-M117L-M216L, D127P-M211 L-P212D-Y89A-M117V-M216A, D127P-M211 L- P212D-Y89A-M117V-M216F, D127P-M211 L-P212D-Y89A-M117V-M216L, D127P-M211 L-P212D- M117A, D127P-M211 L-P212D-M117F, D127P-M211 L-P212D-M1171, D127P-M211 L-P212D-M117L, D127P-M211 L-P212D-M117 V, D127P-M211 L-P212D-M117A-M216A, D127P-M211 L-P212D-M117A- M216F, D127P-M211 L-P212D-M117A-M216L, D127P-M211 L-P212D-M117F-M216A, D127P-M211 L- P212D-M117F-M216F, D127P-M211 L-P212D-M117F-M216L, D127P-M211 L-P212D-M117I-M216A, D127P-M211 L-P212D-M117I-M216F, D127P-M211 L-P212D-M117I-M216L, D127P-M211 L-P212D- M117L-M216A, D127P-M211 L-P212D-M117L-M216F, D127P-M211 L-P212D-M117L-M216L, D127P- M211 L-P212D-M117V-M216A, D127P-M211 L-P212D-M117V-M216F, D127P-M211 L-P212D-M117V- M216L, D127P-M211 L-P212D-M216A, D127P-M211 L-P212D-M216F, D127P-M211 L-P212D-M216L, P212H-A29G, P212H-A29G-D58P, P212H-A29G-Y89A, P212H-A29G-M117A, P212H-A29G-M117F, P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H- A29G-M216F, P212H-A29G-M216L, P212H-A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H- A29G-D58P-M117F, P212H-A29G-D58P-M1171, P212H-A29G-D58P-M117L, P212H-A29G-D58P- M117V, P212H-A29G-D58P-M216A, P212H-A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A-M117F, P212H-A29G-Y89A-M1171, P212H-A29G- Y89A-M117L, P212H-A29G-Y89A-M117V, P212H-A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A-M216A, P212H-A29G-M117A-M216F, P212H- A29G-M117A-M216L, P212H-A29G-D58P-Y89A-M117A, P212H-A29G-D58P-Y89A-M117F, P212H- A29G-D58P-Y89A-M1171, P212H-A29G-D58P-Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G-D58P-Y89A-M216F, P212H-A29G-D58P-Y89A- M216L, P212H-A29G-Y89A-M117A-M216A, P212H-A29G-Y89A-M117A-M216F, P212H-A29G-Y89A- M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H- A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M117I-M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A-M117L-M216A, P212H-A29G-Y89A-M117L- M216F, P212H-A29G-Y89A-M117L-M216L, P212H-A29G-Y89A-M117V-M216A, P212H-A29G-Y89A- M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P- M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H-D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M1171, P212H-D58P-Y89A-M117L, P212H-D58P- Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P-Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A-M216F, P212H-D58P-M117A-M216L, P212H- D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P- M117I-M216A, P212H-D58P-M117I-M216F, P212H-D58P-M117I-M216L, P212H-D58P-M117L- M216A, P212H-D58P-M117L-M216F, P212H-D58P-M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V-M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H-Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A- M216A, P212H-Y89A-M216F, P212H-Y89A-M216L, P212H-Y89A-M117A-M216A, P212H-Y89A- M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F- M216F, P212H-Y89A-M117F-M216L, P212H-Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L-M216A, P212H-Y89A-M117L-M216F, P212H- Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A- M117V-M216L, P212H-M117A, P212H-M117F, P212H-M1171, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H-M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I-M216A, P212H-M117I-M216F, P212H- M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V- M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H- M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S-A29G-D58P, Q12L-M122L-A222S-A29G- Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L-A222S-A29G-M117F, Q12L-M122L-A222S- A29G-M117I, Q12L-M122L-A222S-A29G-M117L, Q12L-M122L-A222S-A29G-M117V, Q12L-M122L- A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L- M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S-A29G-D58P-M117A, Q12L-M122L-A222S- A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P-M117I, Q12L-M122L-A222S-A29G-D58P- M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L-M122L-A222S-A29G-D58P-M216A, Q12L- M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S-A29G-D58P-M216L, Q12L-M122L-A222S- A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A-M117F, Q12L-M122L-A222S-A29G-Y89A- M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L-M122L-A222S-A29G-Y89A-M117V, Q12L- M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S-A29G-Y89A-M216F, Q12L-M122L-A222S- A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A-M216A, Q12L-M122L-A222S-A29G-M117A- M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M1171, Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S-D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L-A222S-D58P-M1171, Q12L-M122L-A222S-D58P- M117L, Q12L-M122L-A222S-D58P-M117V, Q12L-M122L-A222S-D58P-M216A, Q12L-M122L-A222S- D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L- M122L-A222S-D58P-Y89A-M117F, Q12L-M122L-A222S-D58P-Y89A-M1171, Q12L-M122L-A222S- D58P-Y89A-M117L, Q12L-M122L-A222S-D58P-Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A- M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L- M122L-A222S-D58P-M117A-M216A, Q12L-M122L-A222S-D58P-M117A-M216F, Q12L-M122L- A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P-M117F-M216A, Q12L-M122L-A222S-D58P- M117F-M216F, Q12L-M122L-A222S-D58P-M117F-M216L, Q12L-M122L-A222S-D58P-M1171- M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L-M122L-A222S-D58P-M117I-M216L, Q12L- M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S-D58P-M117L-M216F, Q12L-M122L- A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V-M216A, Q12L-M122L-A222S-D58P- M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L- A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L- M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A-M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S-Y89A-M216L, Q12L-M122L-A222S-Y89A- M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A- M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L-A222S-Y89A-M117F-M216F, Q12L- M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A-M117I-M216A, Q12L-M122L-A222S- Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L- M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L-A222S-Y89A-M117L-M216L, Q12L- M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A-M117V-M216F, Q12L-M122L- A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L-M122L-A222S-M117F, Q12L- M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L-A222S-M117V, Q12L-M122L- A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L-M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F-M216F, Q12L-M122L-A222S- M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L-A222S-M117I-M216F, Q12L- M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L- M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S-M117V-M216A, Q12L-M122L- A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L-M122L-A222S-M216A, Q12L- M122L-A222S-M216F, Q12L-M122L-A222S-M216Lbestehenden Gruppe ausgewählt ist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. M211 L-P212D-D58P-Y89A-M1171, D127P-M211 L-P212D-D58P-Y89A-M117L, D127P-M211 L-P212D- D58P-Y89A-M117V, D127P-M211 L-P212D-D58P-Y89A-M216A, D127P-M211 L-P212D-D58P-Y89A-M216F, D127P-M211 L-P212D-D58P-Y89A-M216L, D127P-M211 L-P212D-D58P-M117A-M216A, D127P-M211 L-P212D-D58P-M117A-M216F, D127P-M211 L-P212D-D58P-M117A-M216L, D127P-M211 L-P212D-D58P-M117F-M216A, D127P-M211 L-P212D-D58P-M117F-M216F, D127P-M211 L- P212D-D58P-M117F-M216L, D127P-M211 L-P212D-D58P-M117I-M216A, D127P-M211 L-P212D- D58P-M117I-M216F, D127P-M211 L-P212D-D58P-M117I-M216L, D127P-M211 L-P212D-D58P-M117L-M216A, D127P-M211 L-P212D-D58P-M117L-M216F, D127P-M211 L-P212D-D58P-M117L- M216L, D127P-M211 L-P212D-D58P-M117V-M216A, D127P-M211 L-P212D-D58P-M117V-M216F, D127P-M211 L-P212D-D58P-M117V-M216L, D127P-M211 L-P212D-Y89A, D127P-M211 L-P212D-Y89A-M117A, D127P-M211 L-P212D-Y89A-M117F, D127P-M211 L-P212D-Y89A-M1171, D127P-M211 L-P212D-Y89A-M117L, D127P-M211 L-P212D-Y89A-M117V, D127P-M211 L-P212D-Y89A-M216A, D127P-M211 L-P212D-Y89A-M216F, D127P-M211 L-P212D-Y89A-M216L, D127P-M211 L- P212D-Y89A-M117A-M216A, D127P-M211 L-P212D-Y89A-M117A-M216F, D127P-M211 L-P212D- Y89A-M117A-M216L, D127P-M211 L-P212D-Y89A-M117F-M216A, D127P-M211 L-P212D-Y89A- M117F-M216F, D127P-M211 L-P212D-Y89A-M117F-M216L, D127P-M211 L-P212D-Y89A-M1171- M216A, D127P-M211 L-P212D-Y89A-M117I-M216F, D127P-M211 L-P212D-Y89A-M117I-M216L, D127P-M211 L-P212D-Y89A-M117L-M216A, D127P-M211 L-P212D-Y89A-M117L-M216F, D127P- M211 L-P212D-Y89A-M117L-M216L, D127P-M211 L-P212D-Y89A-M117V-M216A, D127P-M211 L- P212D-Y89A-M117V-M216F, D127P-M211 L-P212D-Y89A-M117V-M216L, D127P-M211 L-P212D-M117A, D127P-M211 L-P212D-M117F, D127P-M211 L-P212D-M1171, D127P-M211 L-P212D-M117L, D127P-M211 L-P212D-M117 V, D127P-M211 L-P212D-M117A-M216A, D127P-M211 L-P212D-M117A- M216F, D127P-M211 L-P212D-M117A-M216L, D127P-M211 L-P212D-M117F-M216A, D127P-M211 L-P212D-M117F-M216F, D127P-M211 L-P212D-M117F-M216L, D127P-M211 L-P212D-M117I-M216A, D127P-M211 L-P212D-M117I-M216F, D127P-M211 L-P212D-M117I-M216L, D127P-M211 L-P212D-M117L-M216A, D127P-M211 L-P212D-M117L-M216F, D127P-M211 L-P212D-M117L-M216L, D127P-M211 L-P212D-M117V-M216A, D127P-M211 L-P212D-M117V-M216F, D127P-M211 L-P212D-M117V- M216L, D127P-M211 L-P212D-M216A, D127P-M211 L-P212D-M216F, D127P-M211 L-P212D-M216L, P212H-A29G, P212H-A29G-D58P, P212H-A29G-Y89A, P212H-A29G-M117A, P212H-A29G-M117F, P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H-A29G-M216F, P212H-A29G-M216L, P212H-A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H-A29G-D58P-M117F, P212H-A29G-D58P-M1171, P212H-A29G-D58P-M117L, P212H-A29G-D58P-M117V, P212H-A29G-D58P-M216A, P212H-A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A-M117F, P212H-A29G-Y89A-M1171, P212H-A29G-Y89A-M117L, P212H-A29G-Y89A-M117V, P212H-A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A-M216A, P212H-A29G-M117A-M216F, P212H-A29G-M117A-M216L, P212H-A29G-D58P-Y89A-M117A, P212H-A29G-D58P-Y89A-M117F, P212H-A29G-D58P-Y89A-M1171, P212H-A29G-D58P-Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G-D58P-Y89A-M216F, P212H-A29G-D58P-Y89A-M216L, P212H-A29G-Y89A-M117A-M216A, P212H-A29G-Y89A-M117A-M216F, P212H-A29G-Y89A-M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H-A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M117I-M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A-M117L-M216A, P212H-A29G-Y89A-M117L-M216F, P212H-A29G-Y89A-M117L-M216L, P212H-A29G-Y89A-M117V-M216A, P212H-A29G-Y89A- M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P-M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H-D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M1171, P212H-D58P-Y89A-M117L, P212H-D58P- Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P-Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A-M216F, P212H-D58P-M117A-M216L, P212H-D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P-M117I-M216A, P212H-D58P-M117I-M216F, P212H-D58P-M117I-M216L, P212H-D58P-M117L-M216A, P212H-D58P-M117L-M216F, P212H-D58P-M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V-M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H-Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A-M216A, P212H-Y89A-M216F, P212H-Y89A-M216L, P212H-Y89A-M117A-M216A, P212H-Y89A- M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F- M216F, P212H-Y89A-M117F-M216L, P212H-Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L-M216A, P212H-Y89A-M117L-M216F, P212H-Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A-M117V-M216L, P212H-M117A, P212H-M117F, P212H-M1171, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H-M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I-M216A, P212H-M117I-M216F, P212H-M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V-M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H-M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S-A29G-D58P, Q12L-M122L-A222S-A29G-Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L-A222S-A29G-M117F, Q12L-M122L-A222S-A29G-M117I, Q12L-M122L-A222S-A29G-M117L, Q12L-M122L-A222S-A29G-M117V, Q12L-M122L-A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S-A29G-D58P-M117A, Q12L-M122L-A222S- A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P-M117I, Q12L-M122L-A222S-A29G-D58P- M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L-M122L-A222S-A29G-D58P-M216A, Q12L- M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S-A29G-D58P-M216L, Q12L-M122L-A222S- A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A-M117F, Q12L-M122L-A222S-A29G-Y89A- M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L-M122L-A222S-A29G-Y89A-M117V, Q12L- M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S-A29G-Y89A-M216F, Q12L-M122L-A222S- A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A-M216A, Q12L-M122L-A222S-A29G-M117A-M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M1171, Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S-D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L-A222S-D58P-M1171, Q12L-M122L-A222S-D58P-M117L, Q12L-M122L-A222S-D58P-M117V, Q12L-M122L-A222S-D58P-M216A, Q12L-M122L-A222S- D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L- M122L-A222S-D58P-Y89A-M117F, Q12L-M122L-A222S-D58P-Y89A-M1171, Q12L-M122L-A222S-D58P-Y89A-M117L, Q12L-M122L-A222S-D58P-Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A- M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L- M122L-A222S-D58P-M117A-M216A, Q12L-M122L-A222S-D58P-M117A-M216F, Q12L-M122L- A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P-M117F-M216A, Q12L-M122L-A222S-D58P- M117F-M216F, Q12L-M122L-A222S-D58P-M117F-M216L, Q12L-M122L-A222S-D58P-M1171-M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L-M122L-A222S-D58P-M117I-M216L, Q12L- M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S-D58P-M117L-M216F, Q12L-M122L- A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V-M216A, Q12L-M122L-A222S-D58P-M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L-A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L- M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A-M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S-Y89A-M216L, Q12L-M122L-A222S-Y89A- M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A-M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L-A222S-Y89A-M117F-M216F, Q12L-M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A-M117I-M216A, Q12L-M122L-A222S-Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L-M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L-A222S-Y89A-M117L-M216L, Q12L-M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A-M117V-M216F, Q12L-M122L- A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L-M122L-A222S-M117F, Q12L-M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L-A222S-M117V, Q12L-M122L-A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L-M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F-M216F, Q12L-M122L-A222S-M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L-A222S-M117I-M216F, Q12L-M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L- M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S-M117V-M216A, Q12L-M122L- A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L-M122L-A222S-M216A, Q12L-M122L-A222S-M216F, Q12L-M122L-A222S-M216L, wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , eine Aminosäuresubstitutionskombination aufweist, die aus der aus M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L- P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D- A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G- M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P- M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D- A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L- P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A- M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D- A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G- D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A- M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L- P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G- D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A- M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L- P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G- Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L- M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L- P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P- M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L- P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M1171, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A- M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D- D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P- M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L- P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L- M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D- D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D- Y89A-M117A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A- M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A- M216F, M211 L-P212D-Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D- Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A- M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L- P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V- M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D- M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F- M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L- P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D- M216A, M211 L-P212D-M216F, M211 L-P212D-M216L bestehenden Gruppe ausgewählt ist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G- M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P- M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A- M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A- M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L- P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G- D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A- M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L-P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G- Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L- P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M1171, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A- M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D- D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P- M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L- P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L- M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D- D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D- Y89A-M117A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A- M216F, M211 L-P212D-Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A- M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V- M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D- M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F- M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L existing group is selected, whereby the Protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , eine Aminosäuresubstitutionskombination aufweist, die aus der aus M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V- M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D- M216F, D58P-M211 L-P212D-M216A und M211 L-P212D-M216L bestehenden Gruppe ausgewählt ist, wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V- M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D- M216F, D58P-M211 L-P212D-M216A and M211 L-P212D-M216L, wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, the stability being determined as described in Example 3.

In besonders bevorzugten Ausführungsformen umfasst die erfindungsgemäße Protease eine Aminosäuresubstitutionskombination, die aus der aus I43V-A29G, I43V-A29G-D58P, I43V-A29G- Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M1171, I43V-A29G-M117L, I43V-A29G- M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V- A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M1171, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P-M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P- M216L, I43V-A29G-Y89A-M117A, I43V-A29G-Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G- Y89A-M117L, I43V-A29G-Y89A-M117V, I43V-A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V- A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A- M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G-D58P-Y89A-M117F, I43V-A29G-D58P-Y89A- M117I, I43V-A29G-D58P-Y89A-M117L, I43V-A29G-D58P-Y89A-M117V, I43V-A29G-D58P-Y89A- M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G-D58P-Y89A-M216L, I43V-A29G-Y89A-M117A- M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G-Y89A-M117A-M216L, I43V-A29G-Y89A- M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V-A29G-Y89A-M117F-M216L, I43V-A29G- Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V-A29G-Y89A-M117I-M216L, I43V-A29G- Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V-A29G-Y89A-M117L-M216L, I43V- A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P-M117F, I43V-D58P-M1171, I43V-D58P- M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P-M216F, I43V-D58P-M216L, I43V-D58P- Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A-M1171, I43V-D58P-Y89A-M117L, I43V- D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P-Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V-D58P-M117A-M216L, I43V-D58P- M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F-M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P-M117L-M216A, I43V-D58P-M117L- M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V- D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A-M117F, I43V-Y89A-M1171, I43V- Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A-M216F, I43V-Y89A-M216L, I43V- Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A-M117A-M216L, I43V-Y89A-M117F- M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V- Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L-M216A, I43V-Y89A-M117L- M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V-Y89A-M117V-M216F, I43V- Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V-M117L, I43V-M117V, I43V- M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F-M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V-M117I-M216L, I43V-M117L- M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V- M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S-T156A-A29G, M122L-N154S- T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S-T156A-A29G-M117A, M122L- N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M117I, M122L-N154S-T156A-A29G- M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A-A29G-M216A, M122L-N154S- T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L-N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A-A29G-D58P-M117F, M122L- N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P-M117L, M122L-N154S-T156A- A29G-D58P-M117V, M122L-N154S-T156A-A29G-D58P-M216A, M122L-N154S-T156A-A29G-D58P- M216F, M122L-N154S-T156A-A29G-D58P-M216L, M122L-N154S-T156A-A29G-Y89A-M117A, M122L-N154S-T156A-A29G-Y89A-M117F, M122L-N154S-T156A-A29G-Y89A-M117I, M122L-N154S- T156A-A29G-Y89A-M117L, M122L-N154S-T156A-A29G-Y89A-M117V, M122L-N154S-T156A-A29G- Y89A-M216A, M122L-N154S-T156A-A29G-Y89A-M216F, M122L-N154S-T156A-A29G-Y89A-M216L, M122L-N154S-T156A-A29G-M117A-M216A, M122L-N154S-T156A-A29G-M117A-M216F, M122L- N154S-T156A-A29G-M117A-M216L, M122L-N154S-T156A-A29G-D58P-Y89A-M117A, M122L- N154S-T156A-A29G-D58P-Y89A-M117F, M122L-N154S-T156A-A29G-D58P-Y89A-M117I, M122L- N154S-T156A-A29G-D58P-Y89A-M117L, M122L-N154S-T156A-A29G-D58P-Y89A-M117V, M122L- N154S-T156A-A29G-D58P-Y89A-M216A, M122L-N154S-T156A-A29G-D58P-Y89A-M216F, M122L- N154S-T156A-A29G-D58P-Y89A-M216L, M122L-N154S-T156A-A29G-Y89A-M117A-M216A, M122L- N154S-T156A-A29G-Y89A-M117A-M216F, M122L-N154S-T156A-A29G-Y89A-M117A-M216L, M122L-N154S-T156A-A29G-Y89A-M117F-M216A, M122L-N154S-T156A-A29G-Y89A-M117F- M216F, M122L-N154S-T156A-A29G-Y89A-M117F-M216L, M122L-N154S-T156A-A29G-Y89A-M117I- M216A, M122L-N154S-T156A-A29G-Y89A-M117I-M216F, M122L-N154S-T156A-A29G-Y89A-M117I- M216L, M122L-N154S-T156A-A29G-Y89A-M117L-M216A, M122L-N154S-T156A-A29G-Y89A- M117L-M216F, M122L-N154S-T156A-A29G-Y89A-M117L-M216L, M122L-N154S-T156A-A29G- Y89A-M117V-M216A, M122L-N154S-T156A-A29G-Y89A-M117V-M216F, M122L-N154S-T156A- A29G-Y89A-M117V-M216L, M122L-N154S-T156A-D58P, M122L-N154S-T156A-D58P-Y89A, M122L- N154S-T156A-D58P-M117A, M122L-N154S-T156A-D58P-M117F, M122L-N154S-T156A-D58P- M117I, M122L-N154S-T156A-D58P-M117L, M122L-N154S-T156A-D58P-M117V, M122L-N154S- T156A-D58P-M216A, M122L-N154S-T156A-D58P-M216F, M122L-N154S-T156A-D58P-M216L, M122L-N154S-T156A-D58P-Y89A-M117A, M122L-N154S-T156A-D58P-Y89A-M117F, M122L-In particularly preferred embodiments, the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M1171, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P-M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P- M216L, I43V-A29G-Y89A-M117A, I43V-A29G-Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G- Y89A-M117L, I43V-A29G-Y89A-M117V, I43V-A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V-A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A- M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G-D58P-Y89A-M117F, I43V-A29G-D58P-Y89A- M117I, I43V-A29G-D58P-Y89A-M117L, I43V-A29G-D58P-Y89A-M117V, I43V-A29G-D58P-Y89A-M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G-D58P-Y89A-M216L, I43V-A29G-Y89A-M117A-M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G-Y89A-M117A-M216L, I43V-A29G-Y89A-M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V-A29G-Y89A-M117F-M216L, I43V-A29G-Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V-A29G-Y89A-M117I-M216L, I43V-A29G- Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V-A29G-Y89A-M117L-M216L, I43V- A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P-M117F, I43V-D58P-M1171, I43V-D58P-M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P-M216F, I43V-D58P-M216L, I43V-D58P-Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A-M1171, I43V-D58P-Y89A-M117L, I43V-D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P-Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V-D58P-M117A-M216L, I43V-D58P- M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F-M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P-M117L-M216A, I43V-D58P-M117L-M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V-D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A-M117F, I43V-Y89A-M1171, I43V- Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A-M216F, I43V-Y89A-M216L, I43V-Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A-M117A-M216L, I43V-Y89A-M117F-M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V- Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L-M216A, I43V-Y89A-M117L-M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V-Y89A-M117V-M216F, I43V-Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V-M117L, I43V-M117V, I43V-M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F-M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V-M117I-M216L, I43V-M117L-M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V-M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S-T156A-A29G, M122L-N154S-T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S-T156A-A29G-M117A, M122L-N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M117I, M122L-N154S-T156A-A29G-M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A-A29G-M216A, M122L-N154S-T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L-N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A-A29G-D58P-M117F, M122L- N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P-M117L, M122L-N154S-T156A- A29G-D58P-M117V, M122L-N154S-T156A-A29G-D58P-M216A, M122L-N154S-T156A-A29G-D58P-M216F, M122L-N154S-T156A-A29G-D58P-M216L, M122L-N154S-T156A-A29G-Y89A-M117A, M122L-N154S-T156A-A29G-Y89A-M117F, M122L-N154S-T156A-A29G-Y89A-M117I, M122L-N154S-T156A-A29G-Y89A-M117L, M122L-N154S-T156A-A29G-Y89A-M117V, M122L-N154S-T156A-A29G-Y89A-M216A, M122L-N154S-T156A-A29G-Y89A-M216F, M122L-N154S-T156A-A29G-Y89A-M216L, M122L-N154S-T156A-A29G-M117A-M216A, M122L-N154S-T156A-A29G-M117A-M216F, M122L-N154S-T156A-A29G-M117A-M216L, M122L-N154S-T156A-A29G-D58P-Y89A-M117A, M122L-N154S-T156A-A29G-D58P-Y89A-M117F, M122L-N154S-T156A-A29G-D58P-Y89A-M117I, M122L N154S-T156A-A29G-D58P-Y89A-M117L, M122L-N154S-T156A-A29G-D58P-Y89A-M117V, M122L-N154S-T156A-A29G-D58P-Y89A-M216A, M122L-N154S-T156A-A29G-D58P-Y89A-M216F, M122L-N154S-T156A-A29G-D58P-Y89A-M216L, M122L-N154S-T156A-A29G-Y89A-M117A-M216A, M122L N154S-T156A-A29G-Y89A-M117A-M216F, M122L-N154S-T156A-A29G-Y89A-M117A-M216L, M122L-N154S-T156A-A29G-Y89A-M117F-M216A, M122L-N154S-T156A-A29G-Y89A-M117F- M216F, M122L-N154S-T156A-A29G-Y89A-M117F-M216L, M122L-N154S-T156A-A29G-Y89A-M117I- M216A, M122L-N154S-T156A-A29G-Y89A-M117I-M216F, M122L-N154S-T156A-A29G-Y89A-M117I-M216L, M122L-N154S-T156A-A29G-Y89A-M117L-M216A, M122L-N154S-T156A-A29G-Y89A-M117L-M216F, M122L-N154S-T156A-A29G-Y89A-M117L-M216L, M122L-N154S-T156A-A29G-Y89A-M117V-M216A, M122L-N154S-T156A-A29G-Y89A-M117V-M216F, M122L-N154S-T156A- A29G-Y89A-M117V-M216L, M122L-N154S-T156A-D58P, M122L-N154S-T156A-D58P-Y89A, M122L-N154S-T156A-D58P-M117A, M122L-N154S-T156A-D58P-M117F, M122L-N154S-T156A-D58P-M117I, M122L-N154S-T156A-D58P-M117L, M122L-N154S-T156A-D58P-M117V, M122L-N154S-T156A-D58P-M216A, M122L-N154S-T156A-D58P-M216F, M122L-N154S-T156A-D58P-M216L, M122L-N154S-T156A-D58P-Y89A-M117A, M122L-N154S-T156A-D58P-Y89A-M117F, M122L-

N154S-T156A-D58P-Y89A-M117I, M122L-N154S-T156A-D58P-Y89A-M117L, M122L-N154S-T156A- D58P-Y89A-M117V, M122L-N154S-T156A-D58P-Y89A-M216A, M122L-N154S-T156A-D58P-Y89A- M216F, M122L-N154S-T156A-D58P-Y89A-M216L, M122L-N154S-T156A-D58P-M117A-M216A, M122L-N154S-T156A-D58P-M117A-M216F, M122L-N154S-T156A-D58P-M117A-M216L, M122L- N154S-T156A-D58P-M117F-M216A, M122L-N154S-T156A-D58P-M117F-M216F, M122L-N154S- T156A-D58P-M117F-M216L, M122L-N154S-T156A-D58P-M117I-M216A, M122L-N154S-T156A- D58P-M117I-M216F, M122L-N154S-T156A-D58P-M117I-M216L, M122L-N154S-T156A-D58P- M117L-M216A, M122L-N154S-T156A-D58P-M117L-M216F, M122L-N154S-T156A-D58P-M117L- M216L, M122L-N154S-T156A-D58P-M117V-M216A, M122L-N154S-T156A-D58P-M117V-M216F, M122L-N154S-T156A-D58P-M117V-M216L, M122L-N154S-T156A-Y89A, M122L-N154S-T156A- Y89A-M117A, M122L-N154S-T156A-Y89A-M117F, M122L-N154S-T156A-Y89A-M1171, M122L- N154S-T156A-Y89A-M117L, M122L-N154S-T156A-Y89A-M117V, M122L-N154S-T156A-Y89A- M216A, M122L-N154S-T156A-Y89A-M216F, M122L-N154S-T156A-Y89A-M216L, M122L-N154S- T156A-Y89A-M117A-M216A, M122L-N154S-T156A-Y89A-M117A-M216F, M122L-N154S-T156A- Y89A-M117A-M216L, M122L-N154S-T156A-Y89A-M117F-M216A, M122L-N 154S-T156A-Y89A- M117F-M216F, M122L-N154S-T156A-Y89A-M117F-M216L, M122L-N154S-T156A-Y89A-M117I- M216A, M122L-N154S-T156A-Y89A-M117I-M216F, M122L-N154S-T156A-Y89A-M117I-M216L, M122L-N154S-T156A-Y89A-M117L-M216A, M122L-N154S-T156A-Y89A-M117L-M216F, M122L- N 154S-T156A-Y89A-M 117L-M216L, M 122L-N 154S-T156A-Y89A-M 117V-M216A, M 122L-N 154S- T156A-Y89A-M117V-M216F, M122L-N154S-T156A-Y89A-M117V-M216L, M122L-N154S-T156A- M117A, M122L-N154S-T156A-M117F, M122L-N154S-T156A-M1171, M122L-N154S-T156A-M117L, M122L-N154S-T156A-M117V, M122L-N154S-T156A-M117A-M216A, M122L-N154S-T156A-M117A- M216F, M122L-N154S-T156A-M117A-M216L, M122L-N154S-T156A-M117F-M216A, M122L-N154S- T156A-M117F-M216F, M122L-N154S-T156A-M117F-M216L, M122L-N154S-T156A-M117I-M216A, M122L-N154S-T156A-M117I-M216F, M122L-N154S-T156A-M117I-M216L, M122L-N154S-T156A- M117L-M216A, M122L-N154S-T156A-M117L-M216F, M122L-N154S-T156A-M117L-M216L, M122L- N154S-T156A-M117V-M216A, M122L-N154S-T156A-M117V-M216F, M122L-N154S-T156A-M117V- M216L, M122L-N154S-T156A-M216A, M122L-N154S-T156A-M216F, M122L-N154S-T156A-M216L, M211 N-P212D-A29G, M211 N-P212D-A29G-D58P, M211 N-P212D-A29G-Y89A, M211 N-P212D- A29G-M117A, M211 N-P212D-A29G-M117F, M211 N-P212D-A29G-M117I, M211 N-P212D-A29G- M117L, M211 N-P212D-A29G-M117V, M211 N-P212D-A29G-M216A, M211 N-P212D-A29G-M216F, M211 N-P212D-A29G-M216L, M211 N-P212D-A29G-D58P-Y89A, M211 N-P212D-A29G-D58P-M117A, M211 N-P212D-A29G-D58P-M117F, M211 N-P212D-A29G-D58P-M117I, M211 N-P212D-A29G-D58P- M117L, M211 N-P212D-A29G-D58P-M117V, M211 N-P212D-A29G-D58P-M216A, M211 N-P212D- A29G-D58P-M216F, M211 N-P212D-A29G-D58P-M216L, M211 N-P212D-A29G-Y89A-M117A, M211 N-P212D-A29G-Y89A-M117F, M211 N-P212D-A29G-Y89A-M1171, M211 N-P212D-A29G-Y89A- M117L, M211 N-P212D-A29G-Y89A-M117V, M211 N-P212D-A29G-Y89A-M216A, M211 N-P212D- A29G-Y89A-M216F, M211 N-P212D-A29G-Y89A-M216L, M211 N-P212D-A29G-M117A-M216A, M211 N-P212D-A29G-M117A-M216F, M211 N-P212D-A29G-M117A-M216L, M211 N-P212D-A29G- D58P-Y89A-M117A, M211 N-P212D-A29G-D58P-Y89A-M117F, M211 N-P212D-A29G-D58P-Y89A- M117I, M211 N-P212D-A29G-D58P-Y89A-M117L, M211 N-P212D-A29G-D58P-Y89A-M117V, M211 N- P212D-A29G-D58P-Y89A-M216A, M211 N-P212D-A29G-D58P-Y89A-M216F, M211 N-P212D-A29G- D58P-Y89A-M216L, M211 N-P212D-A29G-Y89A-M117A-M216A, M211 N-P212D-A29G-Y89A-M117A- M216F, M211 N-P212D-A29G-Y89A-M117A-M216L, M211 N-P212D-A29G-Y89A-M117F-M216A, M211 N-P212D-A29G-Y89A-M117F-M216F, M211 N-P212D-A29G-Y89A-M117F-M216L, M211 N- P212D-A29G-Y89A-M117I-M216A, M211 N-P212D-A29— Y89A-M117I-M216F, M211 N-P212D-A29G- Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L-M216A, M211 N-P212D-A29G-Y89A-M117L- M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 N-P212D-A29G-Y89A-M117V-M216A, M211 N-P212D-A29G-Y89A-M117V-M216F, M211 N-P212D-A29G-Y89A-M117V-M216L, M211 N- P212D-D58P, M211 N-P212D-D58P-Y89A, M211 N-P212D-D58P-M117A, M211 N-P212D-D58P- M117F, M211 N-P212D-D58P-M117I, M211 N-P212D-D58P-M117L, M211 N-P212D-D58P-M117V, M211 N-P212D-D58P-M216A, M211 N-P212D-D58P-M216F, M211 N-P212D-D58P-M216L, M211 N- P212D-D58P-Y89A-M117A, M211 N-P212D-D58P-Y89A-M117F, M211 N-P212D-D58P-Y89A-M117I, M211 N-P212D-D58P-Y89A-M117L, M211 N-P212D-D58P-Y89A-M117V, M211 N-P212D-D58P-Y89A- M216A, M211 N-P212D-D58P-Y89A-M216F, M211 N-P212D-D58P-Y89A-M216L, M211 N-P212D- D58P-M117A-M216A, M211 N-P212D-D58P-M117A-M216F, M211 N-P212D-D58P-M117A-M216L, M211 N-P212D-D58P-M117F-M216A, M211 N-P212D-D58P-M117F-M216F, M211 N-P212D-D58P- M117F-M216L, M211 N-P212D-D58P-M117I-M216A, M211 N-P212D-D58P-M117I-M216F, M211 N- P212D-D58P-M117I-M216L, M211 N-P212D-D58P-M117L-M216A, M211 N-P212D-D58P-M117L- M216F, M211 N-P212D-D58P-M117L-M216L, M211 N-P212D-D58P-M117V-M216A, M211 N-P212D- D58P-M117V-M216F, M211 N-P212D-D58P-M117V-M216L, M211 N-P212D-Y89A, M211 N-P212D- Y89A-M117A, M211 N-P212D-Y89A-M117F, M211 N-P212D-Y89A-M1171, M211 N-P212D-Y89A- M117L, M211 N-P212D-Y89A-M117V, M211 N-P212D-Y89A-M216A, M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 N-P212D-Y89A-M117A-M216A, M211 N-P212D-Y89A-M117A- M216F, M211 N-P212D-Y89A-M117A-M216L, M211 N-P212D-Y89A-M117F-M216A, M211 N-P212D- Y89A-M117F-M216F, M211 N-P212D-Y89A-M117F-M216L, M211 N-P212D-Y89A-M117I-M216A, M211 N-P212D-Y89A-M117I-M216F, M211 N-P212D-Y89A-M117I-M216L, M211 N-P212D-Y89A- M117L-M216A, M211 N-P212D-Y89A-M117L-M216F, M211 N-P212D-Y89A-M117L-M216L, M211 N- P212D-Y89A-M117V-M216A, M211 N-P212D-Y89A-M117V-M216F, M211 N-P212D-Y89A-M117V- M216L, M211 N-P212D-M117A, M211 N-P212D-M117F, M211 N-P212D-M117I, M211 N-P212D- M117L, M211 N-P212D-M117V, M211 N-P212D-M117A-M216A, M211 N-P212D-M117A-M216F, M211 N-P212D-M117A-M216L, M211 N-P212D-M117F-M216A, M211 N-P212D-M117F-M216F, M211 N-P212D-M117F-M216L, M211 N-P212D-M117I-M216A, M211 N-P212D-M117I-M216F, M211 N- P212D-M117I-M216L, M211 N-P212D-M117L-M216A, M211 N-P212D-M117L-M216F, M211 N-P212D- M117L-M216L, M211 N-P212D-M117V-M216A, M211 N-P212D-M117V-M216F, M211 N-P212D- M117V-M216L, M211 N-P212D-M216A, M211 N-P212D-M216F, M211 N-P212D-M216L, M211 L- P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L- P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D- A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D- A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L- P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A- M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A-M117L, M211 L-P212D-A29G- Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L- P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A- M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L- P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A-M1171, M211 L-P212D-A29G- D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A- M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L- P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A-M216F, M211 L-P212D- A29G-Y89A-M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A- M117F-M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L-P212D-A29G-Y89A-M1171- M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L-M216F, M211 L- P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D- A29G-Y89A-M117V-M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 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L-P212D-Y89A-M117L, M211 L-P212D- Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A- M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A-M216F, M211 L-P212D- Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A- M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L- P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V- M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V-M216L, M211L-P212D- M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D-M117A-M216L, M211 L- P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D- M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L- M216A, M211 L-P212D-M117L-M216F, M211 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P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H-A29G-M216F, P212H-A29G-M216L, P212H- A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H-A29G-D58P-M117F, P212H-A29G-D58P- M117I, P212H-A29G-D58P-M117L, P212H-A29G-D58P-M117V, P212H-A29G-D58P-M216A, P212H- A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A- M117F, P212H-A29G-Y89A-M1171, P212H-A29G-Y89A-M117L, P212H-A29G-Y89A-M117V, P212H- A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A- M216A, P212H-A29G-M117A-M216F, P212H-A29G-M117A-M216L, P212H-A29G-D58P-Y89A- M117A, P212H-A29G-D58P-Y89A-M117F, P212H-A29G-D58P-Y89A-M117I, P212H-A29G-D58P- Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G- D58P-Y89A-M216F, P212H-A29G-D58P-Y89A-M216L, P212H-A29G-Y89A-M117A-M216A, P212H- A29G-Y89A-M117A-M216F, P212H-A29G-Y89A-M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H-A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M1171- M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A- M117L-M216A, P212H-A29G-Y89A-M117L-M216F, P212H-A29G-Y89A-M117L-M216L, P212H- A29G-Y89A-M117V-M216A, P212H-A29G-Y89A-M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P-M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H- D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M117I, P212H-D58P-Y89A-M117L, P212H-D58P-Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P- Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A- M216F, P212H-D58P-M117A-M216L, P212H-D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P-M117I-M216A, P212H-D58P-M117I-M216F, P212H- D58P-M117I-M216L, P212H-D58P-M117L-M216A, P212H-D58P-M117L-M216F, P212H-D58P- M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V- M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H- Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A-M216A, P212H-Y89A-M216F, P212H-Y89A- M216L, P212H-Y89A-M117A-M216A, P212H-Y89A-M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F-M216F, P212H-Y89A-M117F-M216L, P212H- Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L- M216A, P212H-Y89A-M117L-M216F, P212H-Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A-M117V-M216L, P212H-M117A, P212H-M117F, P212H- M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H- M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I- M216A, P212H-M117I-M216F, P212H-M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V-M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H-M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S- A29G-D58P, Q12L-M122L-A222S-A29G-Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L- A222S-A29G-M117F, Q12L-M122L-A222S-A29G-M1171, Q12L-M122L-A222S-A29G-M117L, Q12L- M122L-A222S-A29G-M117V, Q12L-M122L-A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S- A29G-D58P-M117A, Q12L-M122L-A222S-A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P- M117I, Q12L-M122L-A222S-A29G-D58P-M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L- M122L-A222S-A29G-D58P-M216A, Q12L-M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S- A29G-D58P-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A- M117F, Q12L-M122L-A222S-A29G-Y89A-M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L- M122L-A222S-A29G-Y89A-M117V, Q12L-M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S- A29G-Y89A-M216F, Q12L-M122L-A222S-A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A- M216A, Q12L-M122L-A222S-A29G-M117A-M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M117I , Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S- D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L- A222S-D58P-M1171, Q12L-M122L-A222S-D58P-M117L, Q12L-M122L-A222S-D58P-M117V, Q12L- M122L-A222S-D58P-M216A, Q12L-M122L-A222S-D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L-M122L-A222S-D58P-Y89A-M117F, Q12L-M122L- A222S-D58P-Y89A-M1171, Q12L-M122L-A222S-D58P-Y89A-M117L, Q12L-M122L-A222S-D58P- Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A-M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L-M122L-A222S-D58P-M117A-M216A, Q12L-M122L- A222S-D58P-M117A-M216F, Q12L-M122L-A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P- M117F-M216A, Q12L-M122L-A222S-D58P-M117F-M216F, Q12L-M122L-A222S-D58P-M117F- M216L, Q12L-M122L-A222S-D58P-M117I-M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L- M122L-A222S-D58P-M117I-M216L, Q12L-M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S- D58P-M117L-M216F, Q12L-M122L-A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V- M216A, Q12L-M122L-A222S-D58P-M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L-A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L-M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A- M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S- Y89A-M216L, Q12L-M122L-A222S-Y89A-M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A-M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L- A222S-Y89A-M117F-M216F, Q12L-M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A- M117I-M216A, Q12L-M122L-A222S-Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L-M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L- A222S-Y89A-M117L-M216L, Q12L-M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A- M117V-M216F, Q12L-M122L-A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L- M122L-A222S-M117F, Q12L-M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L- A222S-M117V, Q12L-M122L-A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L- M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F- M216F, Q12L-M122L-A222S-M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L- A222S-M117I-M216F, Q12L-M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L-M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S- M117V-M216A, Q12L-M122L-A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L- M122L-A222S-M216A, Q12L-M122L-A222S-M216F, Q12L-M122L-A222S-M216L bestehenden Gruppe ausgewählt ist, wobei die Nummerierung jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 ist, wobei die Protease neben den genannten Aminosäuresubstitutionen keine weiteren Änderungen umfasst, und wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. N154S-T156A-D58P-Y89A-M117I, M122L-N154S-T156A-D58P-Y89A-M117L, M122L-N154S-T156A- D58P-Y89A-M117V, M122L-N154S-T156A-D58P-Y89A-M216A, M122L-N154S-T156A-D58P-Y89A-M216F, M122L-N154S-T156A-D58P-Y89A-M216L, M122L-N154S-T156A-D58P-M117A-M216A, M122L-N154S-T156A-D58P-M117A-M216F, M122L-N154S-T156A-D58P-M117A-M216L, M122L-N154S-T156A-D58P-M117F-M216A, M122L-N154S-T156A-D58P-M117F-M216F, M122L-N154S-T156A-D58P-M117F-M216L, M122L-N154S-T156A-D58P-M117I-M216A, M122L-N154S-T156A-D58P-M117I-M216F, M122L-N154S-T156A-D58P-M117I-M216L, M122L-N154S-T156A-D58P-M117L-M216A, M122L-N154S-T156A-D58P-M117L-M216F, M122L-N154S-T156A-D58P-M117L- M216L, M122L-N154S-T156A-D58P-M117V-M216A, M122L-N154S-T156A-D58P-M117V-M216F, M122L-N154S-T156A-D58P-M117V-M216L, M122L-N154S-T156A-Y89A, M122L-N154S-T156A- Y89A-M117A, M122L-N154S-T156A-Y89A-M117F, M122L-N154S-T156A-Y89A-M1171, M122L- N154S-T156A-Y89A-M117L, M122L-N154S-T156A-Y89A-M117V, M122L-N154S-T156A-Y89A-M216A, M122L-N154S-T156A-Y89A-M216F, M122L-N154S-T156A-Y89A-M216L, M122L-N154S- T156A-Y89A-M117A-M216A, M122L-N154S-T156A-Y89A-M117A-M216F, M122L-N154S-T156A- Y89A-M117A-M216L, M122L-N154S-T156A-Y89A-M117F-M216A, M122L-N 154S-T156A-Y89A- M117F-M216F, M122L-N154S-T156A-Y89A-M117F-M216L, M122L-N154S-T156A-Y89A-M117I- M216A, M122L-N154S-T156A-Y89A-M117I-M216F, M122L-N154S-T156A-Y89A-M117I-M216L, M122L-N154S-T156A-Y89A-M117L-M216A, M122L-N154S-T156A-Y89A-M117L-M216F, M122L-N 154S-T156A-Y89A-M 117L-M216L, M 122L-N 154S-T156A-Y89A-M 117V-M216A, M 122L-N 154S-T156A-Y89A-M117V-M216F, M122L-N154S-T156A-Y89A-M117V-M216L, M122L-N154S-T156A- M117A, M122L-N154S-T156A-M117F, M122L-N154S-T156A-M1171, M122L-N154S-T156A-M117L, M122L-N154S-T156A-M117V, M122L-N154S-T156A-M117A-M216A, M122L-N154S-T156A-M117A- M216F, M122L-N154S-T156A-M117A-M216L, M122L-N154S-T156A-M117F-M216A, M122L-N154S- T156A-M117F-M216F, M122L-N154S-T156A-M117F-M216L, M122L-N154S-T156A-M117I-M216A, M122L-N154S-T156A-M117I-M216F, M122L-N154S-T156A-M117I-M216L, M122L-N154S-T156A- M117L-M216A, M122L-N154S-T156A-M117L-M216F, M122L-N154S-T156A-M117L-M216L, M122L- N154S-T156A-M117V-M216A, M122L-N154S-T156A-M117V-M216F, M122L-N154S-T156A-M117V-M216L, M122L-N154S-T156A-M216A, M122L-N154S-T156A-M216F, M122L-N154S-T156A-M216L, M211 N-P212D-A29G, M211 N-P212D-A29G-D58P, M211 N-P212D-A29G-Y89A, M211 N-P212D-A29G-M117A, M211 M211 N-P212D-A29G-M117F N-P212D-A29G-M216F, M211 N-P212D-A29G-M216L, M211 N-P212D-A29G-D58P-Y89A, M211 N-P212D-A29G-D58P-M117A, M211 N-P212D-A29G-D58P-M117F, M211 M211 N-P212D-A29G-D58P-M216F, M211 N-P212D-A29G-D58P-M216L, M211 N-P212D-A29G-Y89A-M117A, M211 N-P212D-A29G-Y89A-M117F, M211 N-P212D-A29G-Y89A-M1171, M211 M211 M211 N-P212D-A29G-M117A-M216L, M211 N-P212D-A29G-M117A-M216L, M211 N-P212D-A29G- D58P-Y89A-M117A, M211 N-P212D-A29G-D58P-Y89A-M117F, M211 N-P212D-A29G-D58P-Y89A- M117I, M211 N-P212D-A29G-D58P-Y89A-M117L, M211 N-P212D-A29G-D58P-Y89A-M117V, M211 N-P212D-A29G-D58P-Y89A-M216A, M211 N-P212D-A29G-D58P-Y89A-M216F, M211 N-P212D-A29G- D58P-Y89A-M216L, M211 N-P212D-A29G-Y89A-M117A-M216A, M211 N-P212D-A29G-Y89A-M117A-M216F, M211 N-P212D-A29G-Y89A-M117A-M216L, M211 N-P212D-A29G-Y89A-M117F-M216A, M211 N-P212D-A29G-Y89A-M117F-M216F, M211 N-P212D-A29G-Y89A-M117F-M216L, M211 Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L-M216A, M211 N-P212D-A29G-Y89A-M117L- M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 M211 N-P212D-A29G-Y89A-M117V-M216F M211 N-P212D-D58P-Y89A, M211 M211 N-P212D-D58P-M117I N-P212D-D58P-M216A, M211 N-P212D-D58P-M216F, M211 N-P212D-D58P-M216L, M211 N-P212D-D58P-Y89A-M117A, M211 N-P212D-D58P-Y89A-M117F, M211 M211 N-P212D-D58P-Y89A-M117I, M211 M211 N-P212D-D58P-Y89A-M216L M211 N-P212D-D58P-M117F-M216L, M211 M211 M211 N-P212D-D58P-M117L-M216F, M211 N-P212D-D58P-M117V-M216L, M211 N-P212D-Y89A, M211 N-P212D-Y89A-M117A, M211 N-P212D-Y89A-M117F, M211 N-P212D-Y89A-M1171, M211 N-P212D-Y89A- M117L, M211 N-P212D-Y89A-M117V, M211 N-P212D-Y89A-M216A, M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 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D127P-M211 L-P212D-A29G- D58P-Y89A, D127P-M211 L-P212D-A29G-D58P-M117A, D127P-M211 L-P212D-A29G-D58P-M117F, D127P-M211 L-P212D-A29G-D58P-M1171, D127P-M211 L-P212D-A29G-D58P-M117L, D127P-M211 L-P212D-A29G-D58P-M117V, D127P-M211 L-P212D-A29G-D58P-M216A, D127P-M211 L- P212D-A29G-D58P-M216F, D127P-M211 L-P212D-A29G-D58P-M216L, D127P-M211 L-P212D- A29G-Y89A-M117A, D127P-M211 L-P212D-A29G-Y89A-M117F, D127P-M211 L-P212D-A29G-Y89A-M117I, D127P-M211 L-P212D-A29G-Y89A-M117L, D127P-M211 L-P212D-A29G-Y89A-M117V, D127P-M211 L-P212D-A29G-Y89A-M216A, D127P-M211 L-P212D-A29G-Y89A-M216F, D127P-M211 L-P212D-A29G-Y89A-M216L, D127P-M211 L-P212D-A29G-M117A-M216A, D127P-M211 L- P212D-A29G-M117A-M216F, D127P-M211 L-P212D-A29G-M117A-M216L, D127P-M211 L-P212D- A29G-D58P-Y89A-M117A, D127P-M211 L-P212D-A29G-D58P-Y89A-M117F, D127P-M211 L-P212D- A29G-D58P-Y89A-M1171, D127P-M211 L-P212D-A29G-D58P-Y89A-M117L, D127P-M211 L-P212D-A29G-D58P-Y89A-M117V, D127P-M211 L-P212D-A29G-D58P-Y89A-M216A, D127P-M211 L-P212D- A29G-D58P-Y89A-M216F, D127P-M211 L-P212D-A29G-D58P-Y89A-M216L, D127P-M211 L-P212D- A29G-Y89A-M117A-M216A, D127P-M211 L-P212D-A29G-Y89A-M117A-M216F, D127P-M211 L- P212D-A29G-Y89A-M117A-M216L, D127P-M211 L-P212D-A29G-Y89A-M117F-M216A, D127P- M211 L-P212D-A29G-Y89A-M117F-M216F, D127P-M211 L-P212D-A29G-Y89A-M117F-M216L, D127P-M211 L-P212D-A29G-Y89A-M117I-M216A, D127P-M211 L-P212D-A29—Y89A-M117I-M216F, D127P-M211 L-P212D-A29G-Y89A-M117I-M216L, D127P-M211 L-P212D-A29G-Y89A-M117L-M216A, D127P-M211 L-P212D-A29G-Y89A-M117L-M216F, D127P-M211 L-P212D-A29G-Y89A-M117L- M216L, D127P-M211 L-P212D-A29G-Y89A-M117V-M216A, D127P-M211 L-P212D-A29G-Y89A- M117V-M216F, D127P-M211 L-P212D-A29G-Y89A-M117V-M216L, D127P-M211 L-P212D-D58P, D127P-M211 L-P212D-D58P-Y89A, D127P-M211 L-P212D-D58P-M117A, D127P-M211 L-P212D-D58P-M117F, D127P-M211 L-P212D-D58P-M117I, D127P-M211 L-P212D-D58P-M117L, D127P- M211 L-P212D-D58P-M117V, D127P-M211 L-P212D-D58P-M216A, D127P-M211 L-P212D-D58P-M216F, D127P-M211 L-P212D-D58P-M216L, D127P-M211 L-P212D-D58P-Y89A-M117A, D127P- M211 L-P212D-D58P-Y89A-M117F, D127P-M211 L-P212D-D58P-Y89A-M117I, D127P-M211 L- P212D-D58P-Y89A-M117L, D127P-M211 L-P212D-D58P-Y89A-M117V, D127P-M211 L-P212D-D58P-Y89A-M216A, D127P-M211 L-P212D-D58P-Y89A-M216F, D127P-M211 L-P212D-D58P-Y89A-M216L, D127P-M211 L-P212D-D58P-M117A-M216A, D127P-M211 L-P212D-D58P-M117A-M216F, D127P-M211 L-P212D-D58P-M117A-M216L, D127P-M211 L-P212D-D58P-M117F-M216A, D127P-M211 L- P212D-D58P-M117F-M216F, D127P-M211 L-P212D-D58P-M117F-M216L, D127P-M211 L-P212D- D58P-M117I-M216A, D127P-M211 L-P212D-D58P-M117I-M216F, D127P-M211 L-P212D-D58P- M117I-M216L, D127P-M211 L-P212D-D58P-M117L-M216A, D127P-M211 L-P212D-D58P-M117L- M216F, D127P-M211 L-P212D-D58P-M117L-M216L, D127P-M211 L-P212D-D58P-M117V-M216A, D127P-M211 L-P212D-D58P-M117V-M216F, D127P-M211 L-P212D-D58P-M117V-M216L, D127P-M211 L-P212D-Y89A, D127P-M211 L-P212D-Y89A-M117A, D127P-M211 L-P212D-Y89A-M117F, D127P-M211 L-P212D-Y89A-M1171, D127P-M211 L-P212D-Y89A-M117L, D127P-M211 L-P212D-Y89A-M117V, D127P-M211 L-P212D-Y89A-M216A, D127P-M211 L-P212D-Y89A-M216F, D127P-M211 L-P212D-Y89A-M216L, D127P-M211 L-P212D-Y89A-M117A-M216A, D127P-M211 L-P212D- Y89A-M117A-M216F, D127P-M211 L-P212D-Y89A-M117A-M216L, D127P-M211 L-P212D-Y89A- M117F-M216A, D127P-M211 L-P212D-Y89A-M117F-M216F, D127P-M211 L-P212D-Y89A-M117F-M216L, D127P-M211 L-P212D-Y89A-M117I-M216A, D127P-M211 L-P212D-Y89A-M117I-M216F, D127P-M211 L-P212D-Y89A-M117I-M216L, D127P-M211 L-P212D-Y89A-M117L-M216A, D127P-M211 L-P212D-Y89A-M117L-M216F, D127P-M211 L-P212D-Y89A-M117L-M216L, D127P-M211 L- P212D-Y89A-M117V-M216A, D127P-M211 L-P212D-Y89A-M117V-M216F, D127P-M211 L-P212D- Y89A-M117V-M216L, D127P-M211 L-P212D-M117A, D127P-M211 L-P212D-M117F, D127P-M211 L-P212D-M117I, D127P-M211 L-P212D-M117L, D127P-M211 L-P212D-M117V, D127P-M211L-P212D-M117A-M216A, D127P-M211 L-P212D-M117A-M216F, D127P-M211 L-P212D-M117A-M216L, D127P-M211 L-P212D-M117F-M216A, D127P-M211 L-P212D-M117F-M216F, D127P-M211 L-P212D-M117F-M216L, D127P-M211 L-P212D-M117I-M216A, D127P-M211 L-P212D-M117I-M216F, D127P-M211 L- P212D-M117I-M216L, D127P-M211 L-P212D-M117L-M216A, D127P-M211 L-P212D-M117L-M216F, D127P-M211 L-P212D-M117L-M216L, D127P-M211 L-P212D-M117V-M216A, D127P-M211 L-P212D- M117V-M216F, D127P-M211 L-P212D-M117V-M216L, D127P-M211 L-P212D-M216A, D127P-M211 L- P212D-M216F, D127P-M211 L-P212D-M216L, P212H-A29G, P212H-A29G-D58P, P212H-A29G-Y89A, P212H-A29G-M117A, P212H-A29G-M117F, P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H-A29G-M216F, P212H-A29G-M216L, P212H-A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H-A29G-D58P-M117F, P212H-A29G-D58P-M117I, P212H-A29G-D58P-M117L, P212H-A29G-D58P-M117V, P212H-A29G-D58P-M216A, P212H- A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A-M117F, P212H-A29G-Y89A-M1171, P212H-A29G-Y89A-M117L, P212H-A29G-Y89A-M117V, P212H-A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A-M216A, P212H-A29G-M117A-M216F, P212H-A29G-M117A-M216L, P212H-A29G-D58P-Y89A-M117A, P212H-A29G-D58P-Y89A-M117F, P212H-A29G-D58P-Y89A-M117I, P212H-A29G-D58P-Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G-D58P-Y89A-M216F, P212H-A29G-D58P-Y89A-M216L, P212H-A29G-Y89A-M117A-M216A, P212H-A29G-Y89A-M117A-M216F, P212H-A29G-Y89A-M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H-A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M1171-M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A-M117L-M216A, P212H-A29G-Y89A-M117L-M216F, P212H-A29G-Y89A-M117L-M216L, P212H-A29G-Y89A-M117V-M216A, P212H-A29G-Y89A-M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P-M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H-D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M117I, P212H-D58P-Y89A-M117L, P212H-D58P-Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P-Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A-M216F, P212H-D58P-M117A-M216L, P212H-D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P-M117I-M216A, P212H-D58P-M117I-M216F, P212H-D58P-M117I-M216L, P212H-D58P-M117L-M216A, P212H-D58P-M117L-M216F, P212H-D58P-M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V-M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H- Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A-M216A, P212H-Y89A-M216F, P212H-Y89A-M216L, P212H-Y89A-M117A-M216A, P212H-Y89A-M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F-M216F, P212H-Y89A-M117F-M216L, P212H-Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L-M216A, P212H-Y89A-M117L-M216F, P212H-Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A-M117V-M216L, P212H-M117A, P212H-M117F, P212H-M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H-M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I-M216A, P212H-M117I-M216F, P212H-M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V-M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H-M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S- A29G-D58P, Q12L-M122L-A222S-A29G-Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L-A222S-A29G-M117F, Q12L-M122L-A222S-A29G-M1171, Q12L-M122L-A222S-A29G-M117L, Q12L-M122L-A222S-A29G-M117V, Q12L-M122L-A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S- A29G-D58P-M117A, Q12L-M122L-A222S-A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P- M117I, Q12L-M122L-A222S-A29G-D58P-M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L- M122L-A222S-A29G-D58P-M216A, Q12L-M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S- A29G-D58P-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A- M117F, Q12L-M122L-A222S-A29G-Y89A-M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L- M122L-A222S-A29G-Y89A-M117V, Q12L-M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S- A29G-Y89A-M216F, Q12L-M122L-A222S-A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A-M216A, Q12L-M122L-A222S-A29G-M117A-M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S- D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L-A222S-D58P-M1171, Q12L-M122L-A222S-D58P-M117L, Q12L-M122L-A222S-D58P-M117V, Q12L-M122L-A222S-D58P-M216A, Q12L-M122L-A222S-D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L-M122L-A222S-D58P-Y89A-M117F, Q12L-M122L-A222S-D58P-Y89A-M1171, Q12L-M122L-A222S-D58P-Y89A-M117L, Q12L-M122L-A222S-D58P-Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A-M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L-M122L-A222S-D58P-M117A-M216A, Q12L-M122L- A222S-D58P-M117A-M216F, Q12L-M122L-A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P-M117F-M216A, Q12L-M122L-A222S-D58P-M117F-M216F, Q12L-M122L-A222S-D58P-M117F-M216L, Q12L-M122L-A222S-D58P-M117I-M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L-M122L-A222S-D58P-M117I-M216L, Q12L-M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S-D58P-M117L-M216F, Q12L-M122L-A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V-M216A, Q12L-M122L-A222S-D58P-M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L-A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L-M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A-M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S-Y89A-M216L, Q12L-M122L-A222S-Y89A-M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A-M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L- A222S-Y89A-M117F-M216F, Q12L-M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A-M117I-M216A, Q12L-M122L-A222S-Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L-M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L- A222S-Y89A-M117L-M216L, Q12L-M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A-M117V-M216F, Q12L-M122L-A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L-M122L-A222S-M117F, Q12L-M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L-A222S-M117V, Q12L-M122L-A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L-M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F- M216F, Q12L-M122L-A222S-M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L- A222S-M117I-M216F, Q12L-M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L-M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S-M117V-M216A, Q12L-M122L-A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L-M122L-A222S-M216A, Q12L-M122L-A222S-M216F, Q12L-M122L-A222S-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO:1, wherein the protease comprises no further changes besides the amino acid substitutions mentioned, and wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, wherein the stability is determined as described in Example 3.

In bevorzugten Ausführungsformen umfasst die erfindungsgemäße Protease eine M211 L-P212D- A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L- P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L-P212D- A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G- M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G- D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D- A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L- P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A-M117L, M211 L-P212D-A29G-Y89A- M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D- A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D- A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A-M117I, M211 L-P212D-A29G-D58P- Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L-P212D- A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A-M216F, M211 L-P212D-A29G-Y89A- M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F- M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L-P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D- A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A- M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V- M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P- Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L- P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L-P212D-D58P-Y89A-M117A, M211 L- P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M117I, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L-P212D-D58P-Y89A- M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D- D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P- M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L-P212D-D58P-M117I-M216L, M211 L- P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L- M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D- D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D-Y89A-M117A, M211 L-P212D-Y89A- M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L- P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A-M216F, M211 L-P212D-Y89A-M117A- M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D- Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A- M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L- P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V-M216L, M211 L-P212D-M117A, M211 L- P212D-M117F, M211 L-P212D-M1171, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D- M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F- M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L- P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D- M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216Lbestehenden Gruppe ausgewählt ist, wobei die Nummerierung jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 ist, wobei die Protease neben den genannten Aminosäuresubstitutionen keine weiteren Änderungen umfasst, und wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention comprises a M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M117I, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G- M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G- D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L- P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A-M117L, M211 L-P212D-A29G-Y89A- M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D- A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A-M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L-P212D- A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A-M216F, M211 L-P212D-A29G-Y89A- M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F- M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L-P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D- A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A- M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V- M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L-P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M117I, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L-P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L- M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D-Y89A-M117A, M211 L-P212D-Y89A- M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A-M216F, M211 L-P212D-Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A- M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V-M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M1171, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L- P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D- M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L, wherein the numbering is based in each case on the numbering according to SEQ ID NO:1, wherein the protease, in addition to the mentioned Amino acid substitutions do not comprise any further changes, and wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen umfasst die erfindungsgemäße Protease eine Aminosäuresubstitutionskombination, die aus der aus M117A-M211 L-P212D, Y89A-M117A-M211 L- P212D, M117V-M211 L-P212D, A29G-M117V-M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L- P212D, M117L-M211 L-P212D, M211 L-P212D-M216F, D58P-M211 L-P212D-M216A und M211 L- P212D-M216L bestehenden Gruppe ausgewählt ist, wobei die Nummerierung jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 ist, wobei die Protease neben den genannten Aminosäuresubstitutionen keine weiteren Änderungen umfasst, und wobei die Protease eine verbesserte Stabilität in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V-M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D-M216F, D58P-M211 L-P212D-M216A and M211 L-P212D-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO:1, wherein the Protease comprises no further changes besides the amino acid substitutions mentioned, and wherein the protease has improved stability in washing or cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens zwei der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino acid substitutions selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 211 und 212 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus M211 N, M211 L, P212D und P212H, vorzugsweise M211 L und/oder P212D, bestehenden Gruppe ausgewählt ist/sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 211 and 212, at least one amino acid substitution selected from the group consisting of M211N, M211L, P212D and P212H, preferably M211L and/or P212D, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, zwei Aminosäuresubstitutionen, die aus der aus M211 N, M211 L, P212D und P212H bestehenden Gruppe ausgewählt sind, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, has two amino acid substitutions selected from the group consisting of M211N, M211L, P212D and P212H, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, has at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, wherein the stability is determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an den Positionen, die den Positionen 211 und 212 entsprechen, die Aminosäuresubstitutionen M211 L und P212D, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at the positions corresponding to positions 211 and 212, the amino acid substitutions M211L and P212D, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H und Q12L-M122L-A222S bestehenden Gruppe ausgewählt ist, und (ii) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus A29G, A29G-D58P, A29G-Y89A, A29G-M117A, A29G-M117F, A29G-M1171, A29G- M117L, A29G-M117V, A29G-M216A, A29G-M216F, A29G-M216L, A29G-D58P-Y89A, A29G-D58P- M117A, A29G-D58P-M117F, A29G-D58P-M1171, A29G-D58P-M117L, A29G-D58P-M117V, A29G- D58P-M216A, A29G-D58P-M216F, A29G-D58P-M216L, A29G-Y89A-M117A, A29G-Y89A-M117F, A29G-Y89A-M1171, A29G-Y89A-M117L, A29G-Y89A-M117V, A29G-Y89A-M216A, A29G-Y89A- M216F, A29G-Y89A-M216L, A29G-M117A-M216A, A29G-M117A-M216F, A29G-M117A-M216L, A29G-D58P-Y89A-M117A, A29G-D58P-Y89A-M117F, A29G-D58P-Y89A-M1171, A29G-D58P-Y89A- M117L, A29G-D58P-Y89A-M117V, A29G-D58P-Y89A-M216A, A29G-D58P-Y89A-M216F, A29G- D58P-Y89A-M216L, A29G-Y89A-M117A-M216A, A29G-Y89A-M117A-M216F, A29G-Y89A-M117A- M216L, A29G-Y89A-M117F-M216A, A29G-Y89A-M117F-M216F, A29G-Y89A-M117F-M216L, A29G- Y89A-M117I-M216A, A29G-Y89A-M117I-M216F, A29G-Y89A-M117I-M216L, A29G-Y89A-M117L- M216A, A29G-Y89A-M117L-M216F, A29G-Y89A-M117L-M216L, A29G-Y89A-M117V-M216A, A29G- Y89A-M117V-M216F, A29G-Y89A-M117V-M216L, D58P, D58P-Y89A, D58P-M117A, D58P-M117F, D58P-M1171, D58P-M117L, D58P-M117V, D58P-M216A, D58P-M216F, D58P-M216L, D58P-Y89A- M117A, D58P-Y89A-M117F, D58P-Y89A-M1171, D58P-Y89A-M117L, D58P-Y89A-M117V, D58P- Y89A-M216A, D58P-Y89A-M216F, D58P-Y89A-M216L, D58P-M117A-M216A, D58P-M117A-M216F, D58P-M117A-M216L, D58P-M117F-M216A, D58P-M117F-M216F, D58P-M117F-M216L, D58P- M117I-M216A, D58P-M117I-M216F, D58P-M117I-M216L, D58P-M117L-M216A, D58P-M117L- M216F, D58P-M117L-M216L, D58P-M117V-M216A, D58P-M117V-M216F, D58P-M117V-M216L, Y89A, Y89A-M117A, Y89A-M117F, Y89A-M1171, Y89A-M117L, Y89A-M117V, Y89A-M216A, Y89A- M216F, Y89A-M216L, Y89A-M117A-M216A, Y89A-M117A-M216F, Y89A-M117A-M216L, Y89A- M117F-M216A, Y89A-M117F-M216F, Y89A-M117F-M216L, Y89A-M117I-M216A, Y89A-M117I- M216F, Y89A-M117I-M216L, Y89A-M117L-M216A, Y89A-M117L-M216F, Y89A-M117L-M216L, Y89A-M117V-M216A, Y89A-M117V-M216F, Y89A-M117V-M216L, M117A, M117F, M117I, M117L, M117V, M117A-M216A, M117A-M216F, M117A-M216L, M117F-M216A, M117F-M216F, M117F- M216L, M117I-M216A, M117I-M216F, M117I-M216L, M117L-M216A, M117L-M216F, M117L-M216L, M117V-M216A, M117V-M216F, M117V-M216L, M216A, M216F, M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H and Q12L-M122L-A222S, and (ii) an amino acid substitution or amino acid substitution combination selected from the group consisting of A29G, A29G-D58P, A29G-Y89A, A29G-M117A, A29G-M117F, A29G-M1171, A29G- M117L, A29G-M117V, A29G-M216A, A29G-M216F, A29G-M216L, A29G-D58P-Y89A, A29G-D58P-M117A, A29G-D58P-M117F, A29G-D58P-M1171, A29G-D58P-M117L, A29G-D58P-M117V, A29G-D58P-M216A, A29G-D58P-M216F, A29G-D58P-M216L, A29G-Y89A-M117A, A29G-Y89A-M117F, A29G-Y89A-M1171, A29G-Y89A-M117L, A29G-Y89A-M117V, A29G-Y89A-M216A, A29G-Y89A-M216F, A29G-Y89A-M216L, A29G-M117A-M216A, A29G-M117A-M216F, A29G-M117A-M216L, A29G-D58P-Y89A-M117A, A29G-D58P-Y89A-M117F, A29G-D58P-Y89A-M1171, A29G-D58P-Y89A-M117L, A29G-D58P-Y89A-M117V, A29G-D58P-Y89A-M216A, A29G-D58P-Y89A-M216F, A29G-D58P-Y89A-M216L, A29G-Y89A-M117A-M216A, A29G-Y89A-M117A-M216F, A29G-Y89A-M117A-M216L, A29G-Y89A-M117F-M216A, A29G-Y89A-M117F-M216F, A29G-Y89A-M117F-M216L, A29G-Y89A-M117I-M216A, A29G-Y89A-M117I-M216F, A29G-Y89A-M117I-M216L, A29G-Y89A-M117L- M216A, A29G-Y89A-M117L-M216F, A29G-Y89A-M117L-M216L, A29G-Y89A-M117V-M216A, A29G- Y89A-M117V-M216F, A29G-Y89A-M117V-M216L, D58P, D58P-Y89A, D58P-M117A, D58P-M117F, D58P-M1171, D58P-M117L, D58P-M117V, D58P-M216A, D58P-M216F, D58P-M216L, D58P-Y89A-M117A, D58P-Y89A-M117F, D58P-Y89A-M1171, D58P-Y89A-M117L, D58P-Y89A-M117V, D58P-Y89A-M216A, D58P-Y89A-M216F, D58P-Y89A-M216L, D58P-M117A-M216A, D58P-M117A-M216F, D58P-M117A-M216L, D58P-M117F-M216A, D58P-M117F-M216F, D58P-M117F-M216L, D58P- M117I-M216A, D58P-M117I-M216F, D58P-M117I-M216L, D58P-M117L-M216A, D58P-M117L-M216F, D58P-M117L-M216L, D58P-M117V-M216A, D58P-M117V-M216F, D58P-M117V-M216L, Y89A, Y89A-M117A, Y89A-M117F, Y89A-M1171, Y89A-M117L, Y89A-M117V, Y89A-M216A, Y89A-M216F, Y89A-M216L, Y89A-M117A-M216A, Y89A-M117A-M216F, Y89A-M117A-M216L, Y89A-M117F-M216A, Y89A-M117F-M216F, Y89A-M117F-M216L, Y89A-M117I-M216A, Y89A-M117I-M216F, Y89A-M117I-M216L, Y89A-M117L-M216A, Y89A-M117L-M216F, Y89A-M117L-M216L, Y89A-M117V-M216A, Y89A-M117V-M216F, Y89A-M117V-M216L, M117A, M117F, M117I, M117L, M117V, M117A-M216A, M117A-M216F, M117A-M216L, M117F-M216A, M117F-M216F, M117F-M216L, M117I-M216A, M117I-M216F, M117I-M216L, M117L-M216A, M117L-M216F, M117L-M216L, M117V-M216A, M117V-M216F, M117V-M216L, M216A, M216F, M216L, wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H und Q12L-M122L-A222S bestehenden Gruppe ausgewählt ist, und (ii) eine Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination, die aus der aus M117A, M117A-Y89L, M117V, M117V-A29G, M117F, M117I, M117L, M216F, D58P- M216A, M216L bestehenden Gruppe ausgewählt ist, aufweist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, (i) an amino acid substitution or amino acid substitution combination selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H and Q12L-M122L-A222S, and (ii) an amino acid substitution or amino acid substitution combination selected from the group consisting of M117A, M117A-Y89L, M117V, M117V-A29G, M117F, M117I, M117L, M216F, D58P- M216A, M216L, wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , eine Aminosäuresubstitutionskombination aufweist, die aus der aus I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M117I, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P- M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P-M216L, I43V-A29G-Y89A-M117A, I43V-A29G- Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G-Y89A-M117L, I43V-A29G-Y89A-M117V, I43V- A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V-A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A-M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G- D58P-Y89A-M117F, I43V-A29G-D58P-Y89A-M1171, I43V-A29G-D58P-Y89A-M117L, I43V-A29G- D58P-Y89A-M117V, I43V-A29G-D58P-Y89A-M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G- D58P-Y89A-M216L, I43V-A29G-Y89A-M117A-M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G- Y89A-M117A-M216L, I43V-A29G-Y89A-M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V- A29G-Y89A-M117F-M216L, I43V-A29G-Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V- A29G-Y89A-M117I-M216L, I43V-A29G-Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V- A29G-Y89A-M117L-M216L, I43V-A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P- M117F, I43V-D58P-M1171, I43V-D58P-M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P- M216F, I43V-D58P-M216L, I43V-D58P-Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A- M117I, I43V-D58P-Y89A-M117L, I43V-D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P- Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V- D58P-M117A-M216L, I43V-D58P-M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F- M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P- M117L-M216A, I43V-D58P-M117L-M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V-D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A- M117F, I43V-Y89A-M1171, I43V-Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A- M216F, I43V-Y89A-M216L, I43V-Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A- M117A-M216L, I43V-Y89A-M117F-M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V-Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L- M216A, I43V-Y89A-M117L-M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V- Y89A-M117V-M216F, I43V-Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V- M117L, I43V-M117V, I43V-M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F- M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V- M117I-M216L, I43V-M117L-M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V-M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S- T156A-A29G, M122L-N154S-T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S- T156A-A29G-M117A, M122L-N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M1171, M122L-N154S-T156A-A29G-M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A- A29G-M216A, M122L-N154S-T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L- N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A- A29G-D58P-M117F, M122L-N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P- M117L, M122L-N154S-T156A-A29G-D58P-M117V, M122L-N154S-T156A-A29G-D58P-M216A, M122L-N154S-T156A-A29G-D58P-M216F, M122L-N154S-T156A-A29G-D58P-M216L, M122L- N154S-T156A-A29G-Y89A-M117A, M122L-N154S-T156A-A29G-Y89A-M117F, M122L-N154S- T156A-A29G-Y89A-M117I, M122L-N154S-T156A-A29G-Y89A-M117L, M122L-N154S-T156A-A29G- Y89A-M117V, M122L-N154S-T156A-A29G-Y89A-M216A, M122L-N154S-T156A-A29G-Y89A-M216F, M122L-N154S-T156A-A29G-Y89A-M216L, M122L-N154S-T156A-A29G-M117A-M216A, M122L- N154S-T156A-A29G-M117A-M216F, M122L-N154S-T156A-A29G-M117A-M216L, M122L-N154S- T156A-A29G-D58P-Y89A-M117A, M122L-N154S-T156A-A29G-D58P-Y89A-M117F, M122L-N154S- T156A-A29G-D58P-Y89A-M1171, M122L-N154S-T156A-A29G-D58P-Y89A-M117L, M122L-N154S- T156A-A29G-D58P-Y89A-M117V, M122L-N154S-T156A-A29G-D58P-Y89A-M216A, M122L-N154S- T156A-A29G-D58P-Y89A-M216F, M122L-N154S-T156A-A29G-D58P-Y89A-M216L, M122L-N154S- T156A-A29G-Y89A-M117A-M216A, M122L-N154S-T156A-A29G-Y89A-M117A-M216F, M122L- N154S-T156A-A29G-Y89A-M117A-M216L, M122L-N154S-T156A-A29G-Y89A-M117F-M216A, M122L-N154S-T156A-A29G-Y89A-M117F-M216F, M122L-N154S-T156A-A29G-Y89A-M117F- M216L, M122L-N154S-T156A-A29G-Y89A-M117I-M216A, M122L-N154S-T156A-A29G-Y89A-M1171- M216F, M122L-N154S-T156A-A29G-Y89A-M117I-M216L, M122L-N154S-T156A-A29G-Y89A-M117L- M216A, M122L-N154S-T156A-A29G-Y89A-M117L-M216F, M122L-N154S-T156A-A29G-Y89A- M117L-M216L, M122L-N154S-T156A-A29G-Y89A-M117V-M216A, M122L-N154S-T156A-A29G- Y89A-M117V-M216F, M122L-N154S-T156A-A29G-Y89A-M117V-M216L, M122L-N154S-T156A- D58P, M122L-N154S-T156A-D58P-Y89A, M122L-N154S-T156A-D58P-M117A, M122L-N154S- T156A-D58P-M117F, M122L-N154S-T156A-D58P-M1171, M122L-N154S-T156A-D58P-M117L, M122L-N154S-T156A-D58P-M117V, M122L-N154S-T156A-D58P-M216A, M122L-N154S-T156A- D58P-M216F, M122L-N154S-T156A-D58P-M216L, M122L-N154S-T156A-D58P-Y89A-M117A, M122L-N154S-T156A-D58P-Y89A-M117F, M122L-N154S-T156A-D58P-Y89A-M117I, M122L-N154S- T156A-D58P-Y89A-M117L, M122L-N154S-T156A-D58P-Y89A-M117V, M122L-N154S-T156A-D58P- Y89A-M216A, M122L-N154S-T156A-D58P-Y89A-M216F, M122L-N154S-T156A-D58P-Y89A-M216L, M122L-N154S-T156A-D58P-M117A-M216A, M122L-N154S-T156A-D58P-M117A-M216F, M122L- N154S-T156A-D58P-M117A-M216L, M122L-N154S-T156A-D58P-M117F-M216A, M122L-N154S- T156A-D58P-M117F-M216F, M122L-N154S-T156A-D58P-M117F-M216L, M122L-N154S-T156A- D58P-M117I-M216A, M122L-N154S-T156A-D58P-M117I-M216F, M122L-N154S-T156A-D58P- M117I-M216L, M122L-N154S-T156A-D58P-M117L-M216A, M122L-N154S-T156A-D58P-M117L- M216F, M122L-N154S-T156A-D58P-M117L-M216L, M122L-N154S-T156A-D58P-M117V-M216A, M122L-N154S-T156A-D58P-M117V-M216F, M122L-N154S-T156A-D58P-M117V-M216L, M122L- N154S-T156A-Y89A, M122L-N154S-T156A-Y89A-M117A, M122L-N154S-T156A-Y89A-M117F, M122L-N154S-T156A-Y89A-M117I, M122L-N154S-T156A-Y89A-M117L, M122L-N154S-T156A- Y89A-M117V, M122L-N154S-T156A-Y89A-M216A, M122L-N154S-T156A-Y89A-M216F, M122L- N154S-T156A-Y89A-M216L, M122L-N154S-T156A-Y89A-M117A-M216A, M122L-N154S-T156A- Y89A-M117A-M216F, M122L-N154S-T156A-Y89A-M117A-M216L, M122L-N154S-T156A-Y89A- M117F-M216A, M122L-N154S-T156A-Y89A-M117F-M216F, M122L-N154S-T156A-Y89A-M117F- M216L, M122L-N154S-T156A-Y89A-M117I-M216A, M122L-N154S-T156A-Y89A-M117I-M216F, M122L-N154S-T156A-Y89A-M117I-M216L, M122L-N154S-T156A-Y89A-M117L-M216A, M122L- N154S-T156A-Y89A-M117L-M216F, M122L-N154S-T156A-Y89A-M117L-M216L, M122L-N154S- T156A-Y89A-M117V-M216A, M122L-N154S-T156A-Y89A-M117V-M216F, M122L-N154S-T156A- Y89A-M117V-M216L, M122L-N154S-T156A-M117A, M122L-N154S-T156A-M117F, M122L-N154S- T156A-M117I, M122L-N154S-T156A-M117L, M122L-N154S-T156A-M117V, M122L-N154S-T156A- M117A-M216A, M122L-N154S-T156A-M117A-M216F, M122L-N154S-T156A-M117A-M216L, M122L- N154S-T156A-M117F-M216A, M122L-N154S-T156A-M117F-M216F, M122L-N154S-T156A-M117F- M216L, M122L-N154S-T156A-M117I-M216A, M122L-N154S-T156A-M117I-M216F, M122L-N154S- T156A-M117I-M216L, M122L-N154S-T156A-M117L-M216A, M122L-N154S-T156A-M117L-M216F, M122L-N154S-T156A-M117L-M216L, M122L-N154S-T156A-M117V-M216A, M122L-N154S-T156A- M117V-M216F, M122L-N154S-T156A-M117V-M216L, M122L-N154S-T156A-M216A, M122L-N154S- T156A-M216F, M122L-N154S-T156A-M216L, M211 N-P212D-A29G, M211 N-P212D-A29G-D58P, M211 N-P212D-A29G-Y89A, M211 N-P212D-A29G-M117A, M211 N-P212D-A29G-M117F, M211 N- P212D-A29G-M1171, M211 N-P212D-A29G-M117L, M211 N-P212D-A29G-M117V, M211 N-P212D- A29G-M216A, M211 N-P212D-A29G-M216F, M211 N-P212D-A29G-M216L, M211 N-P212D-A29G- D58P-Y89A, M211 N-P212D-A29G-D58P-M117A, M211 N-P212D-A29G-D58P-M117F, M211 N- P212D-A29G-D58P-M1171, M211 N-P212D-A29G-D58P-M117L, M211 N-P212D-A29G-D58P-M117V, M211 N-P212D-A29G-D58P-M216A, M211 N-P212D-A29G-D58P-M216F, M211 N-P212D-A29G- D58P-M216L, M211 N-P212D-A29G-Y89A-M117A, M211 N-P212D-A29G-Y89A-M117F, M211 N- P212D-A29G-Y89A-M117I, M211 N-P212D-A29G-Y89A-M117L, M211 N-P212D-A29G-Y89A-M117V, M211 N-P212D-A29G-Y89A-M216A, M211 N-P212D-A29G-Y89A-M216F, M211 N-P212D-A29G-Y89A- M216L, M211 N-P212D-A29G-M117A-M216A, M211 N-P212D-A29G-M117A-M216F, M211 N-P212D- A29G-M117A-M216L, M211 N-P212D-A29G-D58P-Y89A-M117A, M211 N-P212D-A29G-D58P-Y89A- M117F, M211 N-P212D-A29G-D58P-Y89A-M117I, M211 N-P212D-A29G-D58P-Y89A-M117L, M211 N- P212D-A29G-D58P-Y89A-M117V, M211 N-P212D-A29G-D58P-Y89A-M216A, M211 N-P212D-A29G- D58P-Y89A-M216F, M211 N-P212D-A29G-D58P-Y89A-M216L, M211 N-P212D-A29G-Y89A-M117A- M216A, M211 N-P212D-A29G-Y89A-M117A-M216F, M211 N-P212D-A29G-Y89A-M117A-M216L, M211 N-P212D-A29G-Y89A-M117F-M216A, M211 N-P212D-A29G-Y89A-M117F-M216F, M211 N- P212D-A29G-Y89A-M117F-M216L, M211 N-P212D-A29G-Y89A-M117I-M216A, M211 N-P212D-A29— Y89A-M117I-M216F, M211 N-P212D-A29G-Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L- M216A, M211 N-P212D-A29G-Y89A-M117L-M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 N-P212D-A29G-Y89A-M117V-M216A, M211 N-P212D-A29G-Y89A-M117V-M216F, M211 N- P212D-A29— Y89A-M117V-M216L, M211 N-P212D-D58P, M211 N-P212D-D58P-Y89A, M211 N- P212D-D58P-M117A, M211 N-P212D-D58P-M117F, M211 N-P212D-D58P-M117I, M211 N-P212D- D58P-M117L, M211 N-P212D-D58P-M117V, M211 N-P212D-D58P-M216A, M211 N-P212D-D58P- M216F, M211 N-P212D-D58P-M216L, M211N-P212D-D58P-Y89A-M117A, M211 N-P212D-D58P- Y89A-M117F, M211 N-P212D-D58P-Y89A-M117I, M211 N-P212D-D58P-Y89A-M117L, M211 N- P212D-D58P-Y89A-M117V, M211 N-P212D-D58P-Y89A-M216A, M211 N-P212D-D58P-Y89A-M216F, M211 N-P212D-D58P-Y89A-M216L, M211 N-P212D-D58P-M117A-M216A, M211 N-P212D-D58P- M117A-M216F, M211 N-P212D-D58P-M117A-M216L, M211 N-P212D-D58P-M117F-M216A, M211 N- P212D-D58P-M117F-M216F, M211 N-P212D-D58P-M117F-M216L, M211 N-P212D-D58P-M1171- M216A, M211 N-P212D-D58P-M117I-M216F, M211 N-P212D-D58P-M117I-M216L, M211 N-P212D- D58P-M117L-M216A, M211 N-P212D-D58P-M117L-M216F, M211 N-P212D-D58P-M117L-M216L, M211 N-P212D-D58P-M117V-M216A, M211 N-P212D-D58P-M117V-M216F, M211 N-P212D-D58P- M117V-M216L, M211 N-P212D-Y89A, M211 N-P212D-Y89A-M117A, M211 N-P212D-Y89A-M117F, M211 N-P212D-Y89A-M117I, M211 N-P212D-Y89A-M117L, M211 N-P212D-Y89A-M117V, M211 N- P212D-Y89A-M216A, M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 N-P212D- Y89A-M117A-M216A, M211 N-P212D-Y89A-M117A-M216F, M211 N-P212D-Y89A-M117A-M216L, M211 N-P212D-Y89A-M117F-M216A, M211 N-P212D-Y89A-M117F-M216F, M211 N-P212D-Y89A- M117F-M216L, M211 N-P212D-Y89A-M117I-M216A, M211 N-P212D-Y89A-M117I-M216F, M211 N- P212D-Y89A-M117I-M216L, M211 N-P212D-Y89A-M117L-M216A, M211 N-P212D-Y89A-M117L- M216F, M211 N-P212D-Y89A-M117L-M216L, M211 N-P212D-Y89A-M117V-M216A, M211 N-P212D- Y89A-M117V-M216F, M211 N-P212D-Y89A-M117V-M216L, M211 N-P212D-M117A, M211 N-P212D- M117F, M211 N-P212D-M117I, M211 N-P212D-M117L, M211 N-P212D-M117V, M211 N-P212D- M117A-M216A, M211 N-P212D-M117A-M216F, M211 N-P212D-M117A-M216L, M211 N-P212D- M117F-M216A, M211 N-P212D-M117F-M216F, M211 N-P212D-M117F-M216L, M211 N-P212D-M1171- M216A, M211 N-P212D-M117I-M216F, M21 1 N-P212D-M117I-M216L, M211 N-P212D-M117L-M216A, M211 N-P212D-M1 17L-M216F, M211 N-P212D-M117L-M216L, M211 N-P212D-M117V-M216A, M211 N-P212D-M1 17V-M216F, M21 1 N-P212D-M117V-M216L, M21 1 N-P212D-M216A, M211 N- P212D-M216F, M21 1 N-P212D-M216L, M21 1 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L- P212D-A29G-Y89A, M21 1 L-P212D-A29G-M117A, M211 L-P212D-A29G-M1 17F, M211 L-P212D- A29G-M117I, M211 L-P212D-A29G-M117L, M21 1 L-P212D-A29G-M117V, M211 L-P212D-A29G- M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P- Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G- D58P-M1171, M21 1 L-P212D-A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D- A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L- P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M1171, M211 L-P212D-A29G-Y89A-M117L, M21 1 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A- M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D- A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M21 1 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D- A29G-D58P-Y89A-M117I , M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P- Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L- P212D-A29G-Y89A-M117A-M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L-P212D- A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A- M1 17F-M216L, M21 1 L-P212D-A29G-Y89A-M117I-M216A, M21 1 L-P212D-A29G-Y89A-M1 17I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L- P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G- Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M21 1 L-P212D-A29G-Y89A- M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M21 1 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M1 17L, M211 L- P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D- D58P-M216L, M211 L-P212D-D58P-Y89A-M1 17A, M211 L-P212D-D58P-Y89A-M117F, M211 L- P212D-D58P-Y89A-M1 171, M21 1 L-P212D-D58P-Y89A-M117L, M21 1 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A- M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M1 17A-M216F, M211 L-P212D- D58P-M1 17A-M216L, M211 L-P212D-D58P-M117F-M216A, M21 1 L-P212D-D58P-M1 17F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P-M1 17I-M216A, M211 L-P212D-D58P- M1 17I-M216F, M211 L-P212D-D58P-M1 17I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L- P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D-D58P-M117V- M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D- Y89A, M211 L-P212D-Y89A-M1 17A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M117I, M21 1 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L- P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L- P212D-Y89A-M117A-M216F, M21 1 L-P212D-Y89A-M1 17A-M216L, M211 L-P212D-Y89A-M117F- M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D- Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A- M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L- P212D-Y89A-M117V-M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A- M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L- P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D- M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V- M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L, G160S-A29G, G160S- A29G-D58P, G160S-A29G-Y89A, G160S-A29G-M117A, G160S-A29G-M117F, G160S-A29G-M1171, G160S-A29G-M117L, G160S-A29G-M117V, G160S-A29G-M216A, G160S-A29G-M216F, G160S- A29G-M216L, G160S-A29G-D58P-Y89A, G160S-A29G-D58P-M117A, G160S-A29G-D58P-M117F, G160S-A29G-D58P-M1171, G160S-A29G-D58P-M117L, G160S-A29G-D58P-M117V, G160S-A29G- D58P-M216A, G160S-A29G-D58P-M216F, G160S-A29G-D58P-M216L, G160S-A29G-Y89A-M117A, G160S-A29G-Y89A-M117F, G160S-A29G-Y89A-M1171, G160S-A29G-Y89A-M117L, G160S-A29G- Y89A-M117V, G160S-A29G-Y89A-M216A, G160S-A29G-Y89A-M216F, G160S-A29G-Y89A-M216L, G160S-A29G-M117A-M216A, G160S-A29G-M117A-M216F, G160S-A29G-M117A-M216L, G160S- A29G-D58P-Y89A-M117A, G160S-A29G-D58P-Y89A-M117F, G160S-A29G-D58P-Y89A-M117I, G160S-A29G-D58P-Y89A-M117L, G160S-A29G-D58P-Y89A-M117V, G160S-A29G-D58P-Y89A- M216A, G160S-A29G-D58P-Y89A-M216F, G160S-A29G-D58P-Y89A-M216L, G160S-A29G-Y89A- M117A-M216A, G160S-A29G-Y89A-M117A-M216F, G160S-A29G-Y89A-M117A-M216L, G160S- A29G-Y89A-M117F-M216A, G160S-A29G-Y89A-M117F-M216F, G160S-A29G-Y89A-M117F-M216L, G160S-A29G-Y89A-M117I-M216A, G160S-A29G-Y89A-M117I-M216F, G160S-A29G-Y89A-M1171- M216L, G160S-A29G-Y89A-M117L-M216A, G160S-A29G-Y89A-M117L-M216F, G160S-A29G-Y89A- M117L-M216L, G160S-A29G-Y89A-M117V-M216A, G160S-A29G-Y89A-M117V-M216F, G160S- A29G-Y89A-M117V-M216L, G160S-D58P, G160S-D58P-Y89A, G160S-D58P-M117A, G160S-D58P- M117F, G160S-D58P-M1171, G160S-D58P-M117L, G160S-D58P-M117V, G160S-D58P-M216A, G160S-D58P-M216F, G160S-D58P-M216L, G160S-D58P-Y89A-M117A, G160S-D58P-Y89A-M117F, G160S-D58P-Y89A-M1171, G160S-D58P-Y89A-M117L, G160S-D58P-Y89A-M117V, G160S-D58P- Y89A-M216A, G160S-D58P-Y89A-M216F, G160S-D58P-Y89A-M216L, G160S-D58P-M117A-M216A, G160S-D58P-M117A-M216F, G160S-D58P-M117A-M216L, G160S-D58P-M117F-M216A, G160S- D58P-M117F-M216F, G160S-D58P-M117F-M216L, G160S-D58P-M117I-M216A, G160S-D58P- M117I-M216F, G160S-D58P-M117I-M216L, G160S-D58P-M117L-M216A, G160S-D58P-M117L- M216F, G160S-D58P-M117L-M216L, G160S-D58P-M117V-M216A, G160S-D58P-M117V-M216F, G160S-D58P-M117V-M216L, G160S-Y89A, G160S-Y89A-M117A, G160S-Y89A-M117F, G160S- Y89A-M117I, G160S-Y89A-M117L, G160S-Y89A-M117V, G160S-Y89A-M216A, G160S-Y89A- M216F, G160S-Y89A-M216L, G160S-Y89A-M117A-M216A, G160S-Y89A-M117A-M216F, G160S- Y89A-M117A-M216L, G160S-Y89A-M117F-M216A, G160S-Y89A-M117F-M216F, G160S-Y89A- M117F-M216L, G160S-Y89A-M117I-M216A, G160S-Y89A-M117I-M216F, G160S-Y89A-M1171- M216L, G160S-Y89A-M117L-M216A, G160S-Y89A-M117L-M216F, G160S-Y89A-M117L-M216L, G160S-Y89A-M117V-M216A, G160S-Y89A-M117V-M216F, G160S-Y89A-M117V-M216L, G160S- M117A, G160S-M117F, G160S-M1171, G160S-M117L, G160S-M117V, G160S-M117A-M216A, G160S-M117A-M216F, G160S-M117A-M216L, G160S-M117F-M216A, G160S-M117F-M216F, G160S-M117F-M216L, G160S-M117I-M216A, G160S-M117I-M216F, G160S-M117I-M216L, G160S- M117L-M216A, G160S-M117L-M216F, G160S-M117L-M216L, G160S-M117V-M216A, G160S- M117V-M216F, G160S-M117V-M216L, G160S-M216A, G160S-M216F, G160S-M216L, D127P- M211 L-P212D-A29G, D127P-M211 L-P212D-A29G-D58P, D127P-M211 L-P212D-A29G-Y89A, D127P-M211 L-P212D-A29G-M117A, D127P-M211 L-P212D-A29G-M117F, D127P-M211 L-P212D- A29G-M117I, D127P-M211 L-P212D-A29G-M117L, D127P-M211 L-P212D-A29G-M117V, D127P- M211 L-P212D-A29G-M216A, D127P-M211 L-P212D-A29G-M216F, D127P-M211 L-P212D-A29G- M216L, D127P-M211 L-P212D-A29G-D58P-Y89A, D127P-M211 L-P212D-A29G-D58P-M117A, D127P-M211 L-P212D-A29G-D58P-M117F, D127P-M211 L-P212D-A29G-D58P-M1171, D127P- M211 L-P212D-A29G-D58P-M117L, D127P-M211 L-P212D-A29G-D58P-M117V, D127P-M211 L- P212D-A29G-D58P-M216A, D127P-M211 L-P212D-A29G-D58P-M216F, D127P-M211 L-P212D- A29G-D58P-M216L, D127P-M211 L-P212D-A29G-Y89A-M117A, D127P-M211 L-P212D-A29G-Y89A- M117F, D127P-M211 L-P212D-A29G-Y89A-M1171, D127P-M211 L-P212D-A29G-Y89A-M117L, D127P-M211 L-P212D-A29G-Y89A-M117V, D127P-M211 L-P212D-A29G-Y89A-M216A, D127P- M211 L-P212D-A29G-Y89A-M216F, D127P-M211 L-P212D-A29G-Y89A-M216L, D127P-M211 L- P212D-A29G-M117A-M216A, D127P-M211 L-P212D-A29G-M117A-M216F, D127P-M211 L-P212D- A29G-M117A-M216L, D127P-M211 L-P212D-A29G-D58P-Y89A-M117A, D127P-M211 L-P212D- A29G-D58P-Y89A-M117F, D127P-M211 L-P212D-A29G-D58P-Y89A-M1171, D127P-M211 L-P212D- A29G-D58P-Y89A-M117L, D127P-M211 L-P212D-A29G-D58P-Y89A-M117V, D127P-M211 L-P212D- A29G-D58P-Y89A-M216A, D127P-M211 L-P212D-A29G-D58P-Y89A-M216F, D127P-M211 L-P212D- A29G-D58P-Y89A-M216L, D127P-M211 L-P212D-A29G-Y89A-M117A-M216A, D127P-M211 L- P212D-A29G-Y89A-M117A-M216F, D127P-M211 L-P212D-A29G-Y89A-M117A-M216L, D127P- M211 L-P212D-A29G-Y89A-M117F-M216A, D127P-M211 L-P212D-A29G-Y89A-M117F-M216F, D127P-M211 L-P212D-A29G-Y89A-M117F-M216L, D127P-M211 L-P212D-A29G-Y89A-M117I-M216A, D127P-M211 L-P212D-A29— Y89A-M117I-M216F, D127P-M211 L-P212D-A29G-Y89A-M117I-M216L, D127P-M211 L-P212D-A29G-Y89A-M117L-M216A, D127P-M211 L-P212D-A29G-Y89A-M117L- M216F, D127P-M211 L-P212D-A29G-Y89A-M117L-M216L, D127P-M211 L-P212D-A29G-Y89A- M117V-M216A, D127P-M211 L-P212D-A29G-Y89A-M117V-M216F, D127P-M211 L-P212D-A29G- Y89A-M117V-M216L, D127P-M211 L-P212D-D58P, D127P-M211 L-P212D-D58P-Y89A, D127P- M211 L-P212D-D58P-M117A, D127P-M211 L-P212D-D58P-M117F, D127P-M211 L-P212D-D58P- M117I, D127P-M211 L-P212D-D58P-M117L, D127P-M211 L-P212D-D58P-M117V, D127P-M211 L- P212D-D58P-M216A, D127P-M211 L-P212D-D58P-M216F, D127P-M211 L-P212D-D58P-M216L, D127P-M211 L-P212D-D58P-Y89A-M117A, D127P-M211 L-P212D-D58P-Y89A-M117F, D127P-In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M117I, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P-M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P-M216L, I43V-A29G-Y89A-M117A, I43V-A29G-Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G-Y89A-M117L, I43V-A29G-Y89A-M117V, I43V-A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V-A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A-M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G-D58P-Y89A-M117F, I43V-A29G-D58P-Y89A-M1171, I43V-A29G-D58P-Y89A-M117L, I43V-A29G-D58P-Y89A-M117V, I43V-A29G-D58P-Y89A-M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G- D58P-Y89A-M216L, I43V-A29G-Y89A-M117A-M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G- Y89A-M117A-M216L, I43V-A29G-Y89A-M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V-A29G-Y89A-M117F-M216L, I43V-A29G-Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V- A29G-Y89A-M117I-M216L, I43V-A29G-Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V-A29G-Y89A-M117L-M216L, I43V-A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P-M117F, I43V-D58P-M1171, I43V-D58P-M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P-M216F, I43V-D58P-M216L, I43V-D58P-Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A- M117I, I43V-D58P-Y89A-M117L, I43V-D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P- Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V-D58P-M117A-M216L, I43V-D58P-M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F-M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P-M117L-M216A, I43V-D58P-M117L-M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V-D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A- M117F, I43V-Y89A-M1171, I43V-Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A- M216F, I43V-Y89A-M216L, I43V-Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A-M117A-M216L, I43V-Y89A-M117F-M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V-Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L-M216A, I43V-Y89A-M117L-M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V-Y89A-M117V-M216F, I43V-Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V-M117L, I43V-M117V, I43V-M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F- M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V-M117I-M216L, I43V-M117L-M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V-M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, 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M122L-N154S-T156A-M117L, M122L-N154S-T156A-M117V, M122L-N154S-T156A- M117A-M216A, M122L-N154S-T156A-M117A-M216F, M122L-N154S-T156A-M117A-M216L, M122L-N154S-T156A-M117F-M216A, M122L-N154S-T156A-M117F-M216F, M122L-N154S-T156A-M117F-M216L, M122L-N154S-T156A-M117I-M216A, M122L-N154S-T156A-M117I-M216F, M122L-N154S-T156A-M117I-M216L, M122L-N154S-T156A-M117L-M216A, M122L-N154S-T156A-M117L-M216F, M122L-N154S-T156A-M117L-M216L, M122L-N154S-T156A-M117V-M216A, M122L-N154S-T156A- M117V-M216F, M122L-N154S-T156A-M117V-M216L, M122L-N154S-T156A-M216A, M122L-N154S-T156A-M216F, M122L-N154S-T156A-M216L, M211 N-P212D-A29G, M211 N-P212D-A29G-D58P, M211 N-P212D-A29G-Y89A, M211 N-P212D-A29G-M117A, M211 N-P212D-A29G-M117F, M211 N-P212D-A29G-M1171, M211 N-P212D-A29G-M117L, M211 N-P212D-A29G-M117V, M211 N-P212D-A29G-M216A, M211 N-P212D-A29G-M216F, M211 N-P212D-A29G-M216L, M211 N-P212D-A29G- D58P-Y89A, M211 N-P212D-A29G-D58P-M117A, M211 N-P212D-A29G-D58P-M117F, M211 N-P212D-A29G-D58P-M1171, M211 M211 N-P212D-A29G-D58P-M216F, M211 N-P212D-A29G-D58P-M216F, M211 N-P212D-A29G- D58P-M216L, M211 N-P212D-A29G-Y89A-M117A, M211 N-P212D-A29G-Y89A-M117F, M211 N-P212D-A29G-Y89A-M117I, M211 N-P212D-A29G-Y89A-M117L, M211 M211 N-P212D-A29G-Y89A-M117V, M211 M211 N-P212D-A29G-D58P-Y89A-M117A, N-P212D-A29G-M117A-M216A, M211 N-P212D-A29G-D58P-Y89A- M117F, M211 N-P212D-A29G-D58P-Y89A-M117I, M211 N-P212D-A29G-D58P-Y89A-M117L, M211 N- P212D-A29G-D58P-Y89A-M117V, M211 N-P212D-A29G-D58P-Y89A-M216A, M211 N-P212D-A29G- D58P-Y89A-M216F, M211 N-P212D-A29G-D58P-Y89A-M216L, M211 N-P212D-A29G-Y89A-M117A- M216A, M211 N-P212D-A29G-Y89A-M117A-M216F, M211 N-P212D-A29G-Y89A-M117A-M216L, M211 N-P212D-A29G-Y89A-M117F-M216A, M211 N-P212D-A29G-Y89A-M117F-M216F, M211 N-P212D-A29G-Y89A-M117F-M216L, M211 N-P212D-A29G-Y89A-M117I-M216A, M211 N-P212D-A29— Y89A-M117I-M216F, M211 N-P212D-A29G-Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L- M216A, M211 N-P212D-A29G-Y89A-M117L-M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 N-P212D-A29G-Y89A-M117V-M216A, M211 N-P212D-A29G-Y89A-M117V-M216F, M211 N- P212D-A29— Y89A-M117V-M216L, M211 N-P212D-D58P, M211 N-P212D-D58P-Y89A, M211 N- P212D-D58P-M117A, M211 M211 N-P212D-D58P-M117F N-P212D-D58P- M216F, M211 N-P212D-D58P-M216L, M211N-P212D-D58P-Y89A-M117A, M211 N-P212D-D58P- Y89A-M117F, M211 N-P212D-D58P-Y89A-M117I, M211 N-P212D-D58P-Y89A-M117L, M211 N-P212D-D58P-Y89A-M117V, M211 N-P212D-D58P-Y89A-M216A, M211 N-P212D-D58P-Y89A-M216F, M211 M211 N-P212D-D58P-M117A-M216L, M211 N-P212D-D58P-M117A-M216L, M211 M211 M211 N-P212D-D58P-M117L-M216F, M211 M211 N-P212D-D58P-M117V-M216L, M211 N-P212D-Y89A, M211 N-P212D-Y89A-M117A, M211 N-P212D-Y89A-M117F, M211 N-P212D-Y89A-M117I, M211 N-P212D-Y89A-M117L, M211 N-P212D-Y89A-M117V, M211 N-P212D-Y89A-M216A, M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 N-P212D-Y89A-M117A-M216A, M211 M211 N-P212D-Y89A-M117F-M216F, M211 N-P212D-Y89A-M117A-M216F, M211 N-P212D-Y89A-M117F-M216L, M211 N-P212D-Y89A-M117I-M216A, M211 N-P212D-Y89A-M117I-M216F, M211 N-P212D-Y89A-M117I-M216L, M211 N-P212D-Y89A-M117L-M216A, M211 N-P212D-Y89A-M117L-M216F, M211 N-P212D-Y89A-M117L-M216L, M211 N-P212D-Y89A-M117V-M216A, M211 N-P212D-Y89A-M117V-M216F, M211 N-P212D-Y89A-M117V-M216L, M211 N-P212D-M117A, M211 N-P212D-M117F, M211 N-P212D-M117I, M211 N-P212D-M117L, M211 N-P212D-M117V, M211 N-P212D- M117A-M216A, M211 N-P212D-M117A-M216F, M211 N-P212D-M117A-M216L, M211 N-P212D- M117F-M216A, M211 N-P212D-M117F-M216F, M211 N-P212D-M117F-M216L, M211 N-P212D-M1171- M216A, M211 N-P212D-M117I-M216F, M21 1 N-P212D-M117I-M216L, M211 N-P212D-M117L-M216A, M211 N-P212D-M1 17L-M216F, M211 N-P212D-M117L-M216L, M211 N-P212D-M117V-M216A, M211 N-P212D-M1 17V-M216F, M21 1 N-P212D-M117V-M216L, M21 1 N-P212D-M216A, M211 N-P212D-M216F, M21 1 N-P212D-M216L, M21 1 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L- P212D-A29G-Y89A, M21 1 L-P212D-A29G-M117A, M211 L-P212D-A29G-M1 17F, M211 L-P212D- A29G-M117I, M211 L-P212D-A29G-M117L, M21 1 L-P212D-A29G-M117V, 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L-P212D-Y89A-M216F, D127P-M211 L-P212D-Y89A-M216L, D127P-M211 L- P212D-Y89A-M117A-M216A, D127P-M211 L-P212D-Y89A-M117A-M216F, D127P-M211 L-P212D- Y89A-M117A-M216L, D127P-M211 L-P212D-Y89A-M117F-M216A, D127P-M211 L-P212D-Y89A- M117F-M216F, D127P-M211 L-P212D-Y89A-M117F-M216L, D127P-M211 L-P212D-Y89A-M1171- M216A, D127P-M211 L-P212D-Y89A-M117I-M216F, D127P-M211 L-P212D-Y89A-M117I-M216L, D127P-M211 L-P212D-Y89A-M117L-M216A, D127P-M211 L-P212D-Y89A-M117L-M216F, D127P- M211 L-P212D-Y89A-M117L-M216L, D127P-M211 L-P212D-Y89A-M117V-M216A, D127P-M211 L- P212D-Y89A-M117V-M216F, D127P-M211 L-P212D-Y89A-M117V-M216L, D127P-M211 L-P212D- M117A, D127P-M211 L-P212D-M117F, D127P-M211 L-P212D-M1171, D127P-M211 L-P212D-M117L, D127P-M211 L-P212D-M117V, D127P-M211 L-P212D-M117A-M216A, D127P-M211 L-P212D-M117A- M216F, D127P-M211 L-P212D-M117A-M216L, D127P-M211 L-P212D-M117F-M216A, D127P-M211 L- P212D-M117F-M216F, D127P-M211 L-P212D-M117F-M216L, D127P-M211 L-P212D-M117I-M216A, D127P-M211 L-P212D-M117I-M216F, D127P-M211 L-P212D-M117I-M216L, D127P-M211 L-P212D- M117L-M216A, D127P-M211 L-P212D-M117L-M216F, D127P-M211 L-P212D-M117L-M216L, D127P- M211 L-P212D-M117V-M216A, D127P-M211 L-P212D-M117V-M216F, D127P-M211 L-P212D-M117V- M216L, D127P-M211 L-P212D-M216A, D127P-M211 L-P212D-M216F, D127P-M211 L-P212D-M216L, P212H-A29G, P212H-A29G-D58P, P212H-A29G-Y89A, P212H-A29G-M117A, P212H-A29G-M117F, P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H- A29G-M216F, P212H-A29G-M216L, P212H-A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H- A29G-D58P-M117F, P212H-A29G-D58P-M1171, P212H-A29G-D58P-M117L, P212H-A29G-D58P- M117V, P212H-A29G-D58P-M216A, P212H-A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A-M117F, P212H-A29G-Y89A-M1171, P212H-A29G- Y89A-M117L, P212H-A29G-Y89A-M117V, P212H-A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A-M216A, P212H-A29G-M117A-M216F, P212H- A29G-M117A-M216L, P212H-A29G-D58P-Y89A-M117A, P212H-A29G-D58P-Y89A-M117F, P212H- A29G-D58P-Y89A-M1171, P212H-A29G-D58P-Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G-D58P-Y89A-M216F, P212H-A29G-D58P-Y89A- M216L, P212H-A29G-Y89A-M117A-M216A, P212H-A29G-Y89A-M117A-M216F, P212H-A29G-Y89A- M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H- A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M117I-M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A-M117L-M216A, P212H-A29G-Y89A-M117L- M216F, P212H-A29G-Y89A-M117L-M216L, P212H-A29G-Y89A-M117V-M216A, P212H-A29G-Y89A- M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P- M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H-D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M1171, P212H-D58P-Y89A-M117L, P212H-D58P- Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P-Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A-M216F, P212H-D58P-M117A-M216L, P212H- D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P- M117I-M216A, P212H-D58P-M117I-M216F, P212H-D58P-M117I-M216L, P212H-D58P-M117L- M216A, P212H-D58P-M117L-M216F, P212H-D58P-M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V-M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H-Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A- M216A, P212H-Y89A-M216F, P212H-Y89A-M216L, P212H-Y89A-M117A-M216A, P212H-Y89A- M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F- M216F, P212H-Y89A-M117F-M216L, P212H-Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L-M216A, P212H-Y89A-M117L-M216F, P212H- Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A- M117V-M216L, P212H-M117A, P212H-M117F, P212H-M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H-M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I-M216A, P212H-M117I-M216F, P212H- M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V- M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H- M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S-A29G-D58P, Q12L-M122L-A222S-A29G- Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L-A222S-A29G-M117F, Q12L-M122L-A222S- A29G-M117I, Q12L-M122L-A222S-A29G-M117L, Q12L-M122L-A222S-A29G-M117V, Q12L-M122L- A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L- M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S-A29G-D58P-M117A, Q12L-M122L-A222S- A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P-M117I, Q12L-M122L-A222S-A29G-D58P- M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L-M122L-A222S-A29G-D58P-M216A, Q12L- M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S-A29G-D58P-M216L, Q12L-M122L-A222S- A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A-M117F, Q12L-M122L-A222S-A29G-Y89A- M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L-M122L-A222S-A29G-Y89A-M117V, Q12L- M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S-A29G-Y89A-M216F, Q12L-M122L-A222S- A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A-M216A, Q12L-M122L-A222S-A29G-M117A- M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M1171, Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S-D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L-A222S-D58P-M1171, Q12L-M122L-A222S-D58P- M117L, Q12L-M122L-A222S-D58P-M117V, Q12L-M122L-A222S-D58P-M216A, Q12L-M122L-A222S- D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L- M122L-A222S-D58P-Y89A-M117F, Q12L-M122L-A222S-D58P-Y89A-M1171, Q12L-M122L-A222S- D58P-Y89A-M117L, Q12L-M122L-A222S-D58P-Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A- M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L- M122L-A222S-D58P-M117A-M216A, Q12L-M122L-A222S-D58P-M117A-M216F, Q12L-M122L- A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P-M117F-M216A, Q12L-M122L-A222S-D58P- M117F-M216F, Q12L-M122L-A222S-D58P-M117F-M216L, Q12L-M122L-A222S-D58P-M1171- M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L-M122L-A222S-D58P-M117I-M216L, Q12L- M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S-D58P-M117L-M216F, Q12L-M122L- A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V-M216A, Q12L-M122L-A222S-D58P- M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L- A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L- M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A-M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S-Y89A-M216L, Q12L-M122L-A222S-Y89A- M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A- M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L-A222S-Y89A-M117F-M216F, Q12L- M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A-M117I-M216A, Q12L-M122L-A222S- Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L- M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L-A222S-Y89A-M117L-M216L, Q12L- M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A-M117V-M216F, Q12L-M122L- A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L-M122L-A222S-M117F, Q12L- M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L-A222S-M117V, Q12L-M122L- A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L-M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F-M216F, Q12L-M122L-A222S- M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L-A222S-M117I-M216F, Q12L- M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L- M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S-M117V-M216A, Q12L-M122L- A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L-M122L-A222S-M216A, Q12L- M122L-A222S-M216F, Q12L-M122L-A222S-M216Lbestehenden Gruppe ausgewählt ist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. M211 L-P212D-D58P-Y89A-M1171, D127P-M211 L-P212D-D58P-Y89A-M117L, D127P-M211 L-P212D- D58P-Y89A-M117V, D127P-M211 L-P212D-D58P-Y89A-M216A, D127P-M211 L-P212D-D58P-Y89A-M216F, D127P-M211 L-P212D-D58P-Y89A-M216L, D127P-M211 L-P212D-D58P-M117A-M216A, D127P-M211 L-P212D-D58P-M117A-M216F, D127P-M211 L-P212D-D58P-M117A-M216L, D127P-M211 L-P212D-D58P-M117F-M216A, D127P-M211 L-P212D-D58P-M117F-M216F, D127P-M211 L- P212D-D58P-M117F-M216L, D127P-M211 L-P212D-D58P-M117I-M216A, D127P-M211 L-P212D- D58P-M117I-M216F, D127P-M211 L-P212D-D58P-M117I-M216L, D127P-M211 L-P212D-D58P-M117L-M216A, D127P-M211 L-P212D-D58P-M117L-M216F, D127P-M211 L-P212D-D58P-M117L-M216L, D127P-M211 L-P212D-D58P-M117V-M216A, D127P-M211 L-P212D-D58P-M117V-M216F, D127P-M211 L-P212D-D58P-M117V-M216L, D127P-M211 L-P212D-Y89A, D127P-M211 L-P212D-Y89A-M117A, D127P-M211 L-P212D-Y89A-M117F, D127P-M211 L-P212D-Y89A-M1171, D127P-M211 L-P212D-Y89A-M117L, D127P-M211 L-P212D-Y89A-M117V, D127P-M211 L-P212D-Y89A-M216A, D127P-M211 L-P212D-Y89A-M216F, D127P-M211 L-P212D-Y89A-M216L, D127P-M211 L- P212D-Y89A-M117A-M216A, D127P-M211 L-P212D-Y89A-M117A-M216F, D127P-M211 L-P212D- Y89A-M117A-M216L, D127P-M211 L-P212D-Y89A-M117F-M216A, D127P-M211 L-P212D-Y89A- M117F-M216F, D127P-M211 L-P212D-Y89A-M117F-M216L, D127P-M211 L-P212D-Y89A-M1171- M216A, D127P-M211 L-P212D-Y89A-M117I-M216F, D127P-M211 L-P212D-Y89A-M117I-M216L, D127P-M211 L-P212D-Y89A-M117L-M216A, D127P-M211 L-P212D-Y89A-M117L-M216F, D127P-M211 L-P212D-Y89A-M117L-M216L, D127P-M211 L-P212D-Y89A-M117V-M216A, D127P-M211 L-P212D-Y89A-M117V-M216F, D127P-M211 L-P212D-Y89A-M117V-M216L, D127P-M211 L-P212D-M117A, D127P-M211 L-P212D-M117F, D127P-M211 L-P212D-M1171, D127P-M211 L-P212D-M117L, D127P-M211 L-P212D-M117V, D127P-M211 L-P212D-M117A-M216A, D127P-M211 L-P212D-M117A-M216F, D127P-M211 L-P212D-M117A-M216L, D127P-M211 L-P212D-M117F-M216A, D127P-M211 L-P212D-M117F-M216F, D127P-M211 L-P212D-M117F-M216L, D127P-M211 L-P212D-M117I-M216A, D127P-M211 L-P212D-M117I-M216F, D127P-M211 L-P212D-M117I-M216L, D127P-M211 L-P212D-M117L-M216A, D127P-M211 L-P212D-M117L-M216F, D127P-M211 L-P212D-M117L-M216L, D127P- M211 L-P212D-M117V-M216A, D127P-M211 L-P212D-M117V-M216F, D127P-M211 L-P212D-M117V- M216L, D127P-M211 L-P212D-M216A, D127P-M211 L-P212D-M216F, D127P-M211 L-P212D-M216L, P212H-A29G, P212H-A29G-D58P, P212H-A29G-Y89A, P212H-A29G-M117A, P212H-A29G-M117F, P212H-A29G-M1171, P212H-A29G-M117L, P212H-A29G-M117V, P212H-A29G-M216A, P212H- A29G-M216F, P212H-A29G-M216L, P212H-A29G-D58P-Y89A, P212H-A29G-D58P-M117A, P212H-A29G-D58P-M117F, P212H-A29G-D58P-M1171, P212H-A29G-D58P-M117L, P212H-A29G-D58P-M117V, P212H-A29G-D58P-M216A, P212H-A29G-D58P-M216F, P212H-A29G-D58P-M216L, P212H-A29G-Y89A-M117A, P212H-A29G-Y89A-M117F, P212H-A29G-Y89A-M1171, P212H-A29G-Y89A-M117L, P212H-A29G-Y89A-M117V, P212H-A29G-Y89A-M216A, P212H-A29G-Y89A-M216F, P212H-A29G-Y89A-M216L, P212H-A29G-M117A-M216A, P212H-A29G-M117A-M216F, P212H-A29G-M117A-M216L, P212H-A29G-D58P-Y89A-M117A, P212H-A29G-D58P-Y89A-M117F, P212H-A29G-D58P-Y89A-M1171, P212H-A29G-D58P-Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G-D58P-Y89A-M216F, P212H-A29G-D58P-Y89A-M216L, P212H-A29G-Y89A-M117A-M216A, P212H-A29G-Y89A-M117A-M216F, P212H-A29G-Y89A-M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H-A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M117I-M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A-M117L-M216A, P212H-A29G-Y89A-M117L- M216F, P212H-A29G-Y89A-M117L-M216L, P212H-A29G-Y89A-M117V-M216A, P212H-A29G-Y89A-M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P-M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H-D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M1171, P212H-D58P-Y89A-M117L, P212H-D58P-Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P-Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A-M216F, P212H-D58P-M117A-M216L, P212H-D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P-M117I-M216A, P212H-D58P-M117I-M216F, P212H-D58P-M117I-M216L, P212H-D58P-M117L- M216A, P212H-D58P-M117L-M216F, P212H-D58P-M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V-M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H-Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A-M216A, P212H-Y89A-M216F, P212H-Y89A-M216L, P212H-Y89A-M117A-M216A, P212H-Y89A-M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F-M216F, P212H-Y89A-M117F-M216L, P212H-Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L-M216A, P212H-Y89A-M117L-M216F, P212H-Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A- M117V-M216L, P212H-M117A, P212H-M117F, P212H-M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H-M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I-M216A, P212H-M117I-M216F, P212H- M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V-M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H-M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S-A29G-D58P, Q12L-M122L-A222S-A29G-Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L-A222S-A29G-M117F, Q12L-M122L-A222S-A29G-M117I, Q12L-M122L-A222S-A29G-M117L, Q12L-M122L-A222S-A29G-M117V, Q12L-M122L-A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S-A29G-D58P-M117A, Q12L-M122L-A222S- A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P-M117I, Q12L-M122L-A222S-A29G-D58P- M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L-M122L-A222S-A29G-D58P-M216A, Q12L-M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S-A29G-D58P-M216L, Q12L-M122L-A222S- A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A-M117F, Q12L-M122L-A222S-A29G-Y89A-M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L-M122L-A222S-A29G-Y89A-M117V, Q12L-M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S-A29G-Y89A-M216F, Q12L-M122L-A222S- A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A-M216A, Q12L-M122L-A222S-A29G-M117A-M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M1171, Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S-D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L-A222S-D58P-M1171, Q12L-M122L-A222S-D58P-M117L, Q12L-M122L-A222S-D58P-M117V, Q12L-M122L-A222S-D58P-M216A, Q12L-M122L-A222S-D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L- M122L-A222S-D58P-Y89A-M117F, Q12L-M122L-A222S-D58P-Y89A-M1171, Q12L-M122L-A222S-D58P-Y89A-M117L, Q12L-M122L-A222S-D58P-Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A-M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L- M122L-A222S-D58P-M117A-M216A, Q12L-M122L-A222S-D58P-M117A-M216F, Q12L-M122L-A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P-M117F-M216A, Q12L-M122L-A222S-D58P-M117F-M216F, Q12L-M122L-A222S-D58P-M117F-M216L, Q12L-M122L-A222S-D58P-M1171-M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L-M122L-A222S-D58P-M117I-M216L, Q12L-M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S-D58P-M117L-M216F, Q12L-M122L- A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V-M216A, Q12L-M122L-A222S-D58P-M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L-A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L-M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A-M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S-Y89A-M216L, Q12L-M122L-A222S-Y89A-M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A-M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L-A222S-Y89A-M117F-M216F, Q12L- M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A-M117I-M216A, Q12L-M122L-A222S-Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L-M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L-A222S-Y89A-M117L-M216L, Q12L- M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A-M117V-M216F, Q12L-M122L-A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L-M122L-A222S-M117F, Q12L-M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L-A222S-M117V, Q12L-M122L-A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L-M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F-M216F, Q12L-M122L-A222S-M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L-A222S-M117I-M216F, Q12L-M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L- M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S-M117V-M216A, Q12L-M122L- A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L-M122L-A222S-M216A, Q12L- M122L-A222S-M216F, Q12L-M122L-A222S-M216Lexisting group selected wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , eine Aminosäuresubstitutionskombination aufweist, die aus der aus M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L- P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D- A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G- M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P- M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D- A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L- P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A- M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D- A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G- D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A- M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L- P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G- D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A- M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L- P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G- Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L- M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L- P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P- M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L- P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M1171, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A- M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D- D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P- M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L- P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L- M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D- D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D- Y89A-M117A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A- M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A- M216F, M211 L-P212D-Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D- Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A- M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L- P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V- M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D- M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F- M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L- P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D- M216A, M211 L-P212D-M216F, M211 L-P212D-M216Lbestehenden Gruppe ausgewählt ist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO: 1, has an amino acid substitution combination which is selected from the group consisting of M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P- M117A, M211 L-P212D-A29G-D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D- A29G-D58P-M117L, M211 L-P212D-A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A- M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D- A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D-A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A- M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L- P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G- D58P-Y89A-M216L, M211 L-P212D-A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A- M216F, M211 L-P212D-A29G-Y89A-M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L- P212D-A29G-Y89A-M117I-M216A, M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G- Y89A-M117I-M216L, M211 L-P212D-A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L- M216F, M211 L-P212D-A29G-Y89A-M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V-M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L-P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M1171, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A- M216A, M211 L-P212D-D58P-Y89A-M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P- M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L-M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D- D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D- Y89A-M117A, M211 L-P212D-Y89A-M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A- M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A- M216F, M211 L-P212D-Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A- M117L-M216A, M211 L-P212D-Y89A-M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V- M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M117I, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F- M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L-P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L- P212D-M117V-M216A, M211 L-P212D-M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L, wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen ist die erfindungsgemäße Protease eine Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91 %, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, und jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , eine Aminosäuresubstitutionskombination aufweist, die aus der aus M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V- M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D- M216F, D58P-M211 L-P212D-M216A und M211 L-P212D-M216L bestehenden Gruppe ausgewählt ist, wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention is a protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length by at least 70% and increasingly preferably by at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, and in each case based on the numbering according to SEQ ID NO:1, has an amino acid substitution combination which is selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V- M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D- M216F, D58P-M211 L-P212D-M216A and M211 L-P212D-M216L, wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In besonders bevorzugten Ausführungsformen umfasst die erfindungsgemäße Protease eine Aminosäuresubstitutionskombination, die aus der aus I43V-A29G, I43V-A29G-D58P, I43V-A29G- Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M1171, I43V-A29G-M117L, I43V-A29G- M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V- A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M1171, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P-M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P- M216L, I43V-A29G-Y89A-M117A, I43V-A29G-Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G- Y89A-M117L, I43V-A29G-Y89A-M117V, I43V-A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V- A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A- M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G-D58P-Y89A-M117F, I43V-A29G-D58P-Y89A- M117I, I43V-A29G-D58P-Y89A-M117L, I43V-A29G-D58P-Y89A-M117V, I43V-A29G-D58P-Y89A- M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G-D58P-Y89A-M216L, I43V-A29G-Y89A-M117A- M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G-Y89A-M117A-M216L, I43V-A29G-Y89A- M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V-A29G-Y89A-M117F-M216L, I43V-A29G- Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V-A29G-Y89A-M117I-M216L, I43V-A29G- Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V-A29G-Y89A-M117L-M216L, I43V- A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P-M117F, I43V-D58P-M1171, I43V-D58P- M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P-M216F, I43V-D58P-M216L, I43V-D58P- Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A-M1171, I43V-D58P-Y89A-M117L, I43V- D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P-Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V-D58P-M117A-M216L, I43V-D58P- M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F-M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P-M117L-M216A, I43V-D58P-M117L- M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V- D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A-M117F, I43V-Y89A-M1171, I43V- Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A-M216F, I43V-Y89A-M216L, I43V- Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A-M117A-M216L, I43V-Y89A-M117F- M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V- Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L-M216A, I43V-Y89A-M117L- M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V-Y89A-M117V-M216F, I43V- Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V-M117L, I43V-M117V, I43V- M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F-M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V-M117I-M216L, I43V-M117L- M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V- M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S-T156A-A29G, M122L-N154S- T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S-T156A-A29G-M117A, M122L- N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M117I, M122L-N154S-T156A-A29G- M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A-A29G-M216A, M122L-N154S- T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L-N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A-A29G-D58P-M117F, M122L- N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P-M117L, M122L-N154S-T156A- A29G-D58P-M117V, M122L-N154S-T156A-A29G-D58P-M216A, M122L-N154S-T156A-A29G-D58P- M216F, M122L-N154S-T156A-A29G-D58P-M216L, M122L-N154S-T156A-A29G-Y89A-M117A, M122L-N154S-T156A-A29G-Y89A-M117F, M122L-N154S-T156A-A29G-Y89A-M117I, M122L-N154S- T156A-A29G-Y89A-M117L, M122L-N154S-T156A-A29G-Y89A-M117V, M122L-N154S-T156A-A29G- Y89A-M216A, M122L-N154S-T156A-A29G-Y89A-M216F, M122L-N154S-T156A-A29G-Y89A-M216L, M122L-N154S-T156A-A29G-M117A-M216A, M122L-N154S-T156A-A29G-M117A-M216F, M122L- N154S-T156A-A29G-M117A-M216L, M122L-N154S-T156A-A29G-D58P-Y89A-M117A, M122L- N154S-T156A-A29G-D58P-Y89A-M117F, M122L-N154S-T156A-A29G-D58P-Y89A-M117I, M122L- N154S-T156A-A29G-D58P-Y89A-M117L, M122L-N154S-T156A-A29G-D58P-Y89A-M117V, M122L- N154S-T156A-A29G-D58P-Y89A-M216A, M122L-N154S-T156A-A29G-D58P-Y89A-M216F, M122L- N154S-T156A-A29G-D58P-Y89A-M216L, M122L-N154S-T156A-A29G-Y89A-M117A-M216A, M122L- N154S-T156A-A29G-Y89A-M117A-M216F, M122L-N154S-T156A-A29G-Y89A-M117A-M216L, M122L-N154S-T156A-A29G-Y89A-M117F-M216A, M122L-N154S-T156A-A29G-Y89A-M117F- M216F, M122L-N154S-T156A-A29G-Y89A-M117F-M216L, M122L-N154S-T156A-A29G-Y89A-M117I- M216A, M122L-N154S-T156A-A29G-Y89A-M117I-M216F, M122L-N154S-T156A-A29G-Y89A-M117I- M216L, M122L-N154S-T156A-A29G-Y89A-M117L-M216A, M122L-N154S-T156A-A29G-Y89A- M117L-M216F, M122L-N154S-T156A-A29G-Y89A-M117L-M216L, M122L-N154S-T156A-A29G- Y89A-M117V-M216A, M122L-N154S-T156A-A29G-Y89A-M117V-M216F, M122L-N154S-T156A- A29G-Y89A-M117V-M216L, M122L-N154S-T156A-D58P, M122L-N154S-T156A-D58P-Y89A, M122L- N154S-T156A-D58P-M117A, M122L-N154S-T156A-D58P-M117F, M122L-N154S-T156A-D58P- M117I, M122L-N154S-T156A-D58P-M117L, M122L-N154S-T156A-D58P-M117V, M122L-N154S- T156A-D58P-M216A, M122L-N154S-T156A-D58P-M216F, M122L-N154S-T156A-D58P-M216L, M122L-N154S-T156A-D58P-Y89A-M117A, M122L-N154S-T156A-D58P-Y89A-M117F, M122L- N154S-T156A-D58P-Y89A-M117I, M122L-N154S-T156A-D58P-Y89A-M117L, M122L-N154S-T156A- D58P-Y89A-M117V, M122L-N154S-T156A-D58P-Y89A-M216A, M122L-N154S-T156A-D58P-Y89A- M216F, M122L-N154S-T156A-D58P-Y89A-M216L, M122L-N154S-T156A-D58P-M117A-M216A, M122L-N154S-T156A-D58P-M117A-M216F, M122L-N154S-T156A-D58P-M117A-M216L, M122L- N154S-T156A-D58P-M117F-M216A, M122L-N154S-T156A-D58P-M117F-M216F, M122L-N154S- T156A-D58P-M117F-M216L, M122L-N154S-T156A-D58P-M117I-M216A, M122L-N154S-T156A- D58P-M117I-M216F, M122L-N154S-T156A-D58P-M117I-M216L, M122L-N154S-T156A-D58P- M117L-M216A, M122L-N154S-T156A-D58P-M117L-M216F, 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N-P212D-A29G-Y89A-M117F-M216F, M211 N-P212D-A29G-Y89A-M117F-M216L, M211 N- P212D-A29G-Y89A-M117I-M216A, M211 N-P212D-A29— Y89A-M117I-M216F, M211 N-P212D-A29G- Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L-M216A, M211 N-P212D-A29G-Y89A-M117L- M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 N-P212D-A29G-Y89A-M117V-M216A, M211 N-P212D-A29G-Y89A-M117V-M216F, M211 N-P212D-A29— Y89A-M117V-M216L, M211 N- P212D-D58P, M211 N-P212D-D58P-Y89A, M211 N-P212D-D58P-M117A, M211 N-P212D-D58P- M117F, M211 N-P212D-D58P-M117I, M211 N-P212D-D58P-M117L, M211 N-P212D-D58P-M117V, M211 N-P212D-D58P-M216A, M211 N-P212D-D58P-M216F, M211 N-P212D-D58P-M216L, M211 N- P212D-D58P-Y89A-M117A, M211 N-P212D-D58P-Y89A-M117F, M211 N-P212D-D58P-Y89A-M117I, M211 N-P212D-D58P-Y89A-M117L, M211 N-P212D-D58P-Y89A-M117V, M211 N-P212D-D58P-Y89A- M216A, M211 N-P212D-D58P-Y89A-M216F, M211 N-P212D-D58P-Y89A-M216L, M211 N-P212D- D58P-M117A-M216A, M211 N-P212D-D58P-M117A-M216F, M211 N-P212D-D58P-M117A-M216L, M211 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M211 N-P212D-Y89A-M117V-M216F, M211 N-P212D-Y89A-M117V- M216L, M211 N-P212D-M117A, M211 N-P212D-M117F, M211 N-P212D-M117I, M211N-P212D- M117L, M211 N-P212D-M117V, M211 N-P212D-M117A-M216A, M211 N-P212D-M117A-M216F, M211 N-P212D-M117A-M216L, M211 N-P212D-M117F-M216A, M211 N-P212D-M117F-M216F, M211 N-P212D-M117F-M216L, M211 N-P212D-M117I-M216A, M211 N-P212D-M117I-M216F, M211 N- P212D-M117I-M216L, M211 N-P212D-M117L-M216A, M211 N-P212D-M117L-M216F, M211 N-P212D- M117L-M216L, M211 N-P212D-M117V-M216A, M211 N-P212D-M117V-M216F, M211 N-P212D- M117V-M216L, M211 N-P212D-M216A, M211 N-P212D-M216F, M211 N-P212D-M216L, M211 L- P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L- P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D- A29G-M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D- A29G-D58P-M117F, M211 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P212H-A29G-D58P-Y89A- M117A, P212H-A29G-D58P-Y89A-M117F, P212H-A29G-D58P-Y89A-M117I, P212H-A29G-D58P- Y89A-M117L, P212H-A29G-D58P-Y89A-M117V, P212H-A29G-D58P-Y89A-M216A, P212H-A29G- D58P-Y89A-M216F, P212H-A29G-D58P-Y89A-M216L, P212H-A29G-Y89A-M117A-M216A, P212H- A29G-Y89A-M117A-M216F, P212H-A29G-Y89A-M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H-A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M1171- M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A- M117L-M216A, P212H-A29G-Y89A-M117L-M216F, P212H-A29G-Y89A-M117L-M216L, P212H- A29G-Y89A-M117V-M216A, P212H-A29G-Y89A-M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P-M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H- D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M117I, P212H-D58P-Y89A-M117L, P212H-D58P-Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P- Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A- M216F, P212H-D58P-M117A-M216L, P212H-D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P-M117I-M216A, P212H-D58P-M117I-M216F, P212H- D58P-M117I-M216L, P212H-D58P-M117L-M216A, P212H-D58P-M117L-M216F, P212H-D58P- M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V- M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H- Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A-M216A, P212H-Y89A-M216F, P212H-Y89A- M216L, P212H-Y89A-M117A-M216A, P212H-Y89A-M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F-M216F, P212H-Y89A-M117F-M216L, P212H- Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L- M216A, P212H-Y89A-M117L-M216F, P212H-Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A-M117V-M216L, P212H-M117A, P212H-M117F, P212H- M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H- M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I- M216A, P212H-M117I-M216F, P212H-M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V-M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H-M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S- A29G-D58P, Q12L-M122L-A222S-A29G-Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L- A222S-A29G-M117F, Q12L-M122L-A222S-A29G-M1171, Q12L-M122L-A222S-A29G-M117L, Q12L- M122L-A222S-A29G-M117V, Q12L-M122L-A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S- A29G-D58P-M117A, Q12L-M122L-A222S-A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P- M117I, Q12L-M122L-A222S-A29G-D58P-M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L- M122L-A222S-A29G-D58P-M216A, Q12L-M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S- A29G-D58P-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A- M117F, Q12L-M122L-A222S-A29G-Y89A-M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L- M122L-A222S-A29G-Y89A-M117V, Q12L-M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S- A29G-Y89A-M216F, Q12L-M122L-A222S-A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A- M216A, Q12L-M122L-A222S-A29G-M117A-M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M117I , Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117V, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S- D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L- A222S-D58P-M1171, Q12L-M122L-A222S-D58P-M117L, Q12L-M122L-A222S-D58P-M117V, Q12L- M122L-A222S-D58P-M216A, Q12L-M122L-A222S-D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L-M122L-A222S-D58P-Y89A-M117F, Q12L-M122L- A222S-D58P-Y89A-M1171, Q12L-M122L-A222S-D58P-Y89A-M117L, Q12L-M122L-A222S-D58P- Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A-M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L-M122L-A222S-D58P-M117A-M216A, Q12L-M122L- A222S-D58P-M117A-M216F, Q12L-M122L-A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P- M117F-M216A, Q12L-M122L-A222S-D58P-M117F-M216F, Q12L-M122L-A222S-D58P-M117F- M216L, Q12L-M122L-A222S-D58P-M117I-M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L- M122L-A222S-D58P-M117I-M216L, Q12L-M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S- D58P-M117L-M216F, Q12L-M122L-A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V- M216A, Q12L-M122L-A222S-D58P-M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L-A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L-M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A- M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S- Y89A-M216L, Q12L-M122L-A222S-Y89A-M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A-M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L- A222S-Y89A-M117F-M216F, Q12L-M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A- M117I-M216A, Q12L-M122L-A222S-Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L-M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L- A222S-Y89A-M117L-M216L, Q12L-M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A- M117V-M216F, Q12L-M122L-A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L- M122L-A222S-M117F, Q12L-M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L- A222S-M117V, Q12L-M122L-A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L- M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F- M216F, Q12L-M122L-A222S-M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L- A222S-M117I-M216F, Q12L-M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L-M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S- M117V-M216A, Q12L-M122L-A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L- M122L-A222S-M216A, Q12L-M122L-A222S-M216F, Q12L-M122L-A222S-M216L bestehenden Gruppe ausgewählt ist, wobei die Nummerierung jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 ist, wobei die Protease neben den genannten Aminosäuresubstitutionen keine weiteren Änderungen umfasst, und wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In particularly preferred embodiments, the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of I43V-A29G, I43V-A29G-D58P, I43V-A29G-Y89A, I43V-A29G-M117A, I43V-A29G-M117F, I43V-A29G-M117I, I43V-A29G-M117L, I43V-A29G-M117V, I43V-A29G-M216A, I43V-A29G-M216F, I43V-A29G-M216L, I43V-A29G-D58P-Y89A, I43V-A29G-D58P-M117A, I43V-A29G-D58P-M117F, I43V-A29G-D58P-M1171, I43V-A29G-D58P-M117L, I43V-A29G-D58P-M117V, I43V-A29G-D58P-M216A, I43V-A29G-D58P-M216F, I43V-A29G-D58P- M216L, I43V-A29G-Y89A-M117A, I43V-A29G-Y89A-M117F, I43V-A29G-Y89A-M1171, I43V-A29G- Y89A-M117L, I43V-A29G-Y89A-M117V, I43V-A29G-Y89A-M216A, I43V-A29G-Y89A-M216F, I43V-A29G-Y89A-M216L, I43V-A29G-M117A-M216A, I43V-A29G-M117A-M216F, I43V-A29G-M117A- M216L, I43V-A29G-D58P-Y89A-M117A, I43V-A29G-D58P-Y89A-M117F, I43V-A29G-D58P-Y89A- M117I, I43V-A29G-D58P-Y89A-M117L, I43V-A29G-D58P-Y89A-M117V, I43V-A29G-D58P-Y89A-M216A, I43V-A29G-D58P-Y89A-M216F, I43V-A29G-D58P-Y89A-M216L, I43V-A29G-Y89A-M117A-M216A, I43V-A29G-Y89A-M117A-M216F, I43V-A29G-Y89A-M117A-M216L, I43V-A29G-Y89A-M117F-M216A, I43V-A29G-Y89A-M117F-M216F, I43V-A29G-Y89A-M117F-M216L, I43V-A29G-Y89A-M117I-M216A, I43V-A29G-Y89A-M117I-M216F, I43V-A29G-Y89A-M117I-M216L, I43V-A29G- Y89A-M117L-M216A, I43V-A29G-Y89A-M117L-M216F, I43V-A29G-Y89A-M117L-M216L, I43V- A29G-Y89A-M117V-M216A, I43V-A29G-Y89A-M117V-M216F, I43V-A29G-Y89A-M117V-M216L, I43V-D58P, I43V-D58P-Y89A, I43V-D58P-M117A, I43V-D58P-M117F, I43V-D58P-M1171, I43V-D58P- M117L, I43V-D58P-M117V, I43V-D58P-M216A, I43V-D58P-M216F, I43V-D58P-M216L, I43V-D58P-Y89A-M117A, I43V-D58P-Y89A-M117F, I43V-D58P-Y89A-M1171, I43V-D58P-Y89A-M117L, I43V-D58P-Y89A-M117V, I43V-D58P-Y89A-M216A, I43V-D58P-Y89A-M216F, I43V-D58P-Y89A-M216L, I43V-D58P-M117A-M216A, I43V-D58P-M117A-M216F, I43V-D58P-M117A-M216L, I43V-D58P-M117F-M216A, I43V-D58P-M117F-M216F, I43V-D58P-M117F-M216L, I43V-D58P-M117I-M216A, I43V-D58P-M117I-M216F, I43V-D58P-M117I-M216L, I43V-D58P-M117L-M216A, I43V-D58P-M117L-M216F, I43V-D58P-M117L-M216L, I43V-D58P-M117V-M216A, I43V-D58P-M117V-M216F, I43V-D58P-M117V-M216L, I43V-Y89A, I43V-Y89A-M117A, I43V-Y89A-M117F, I43V-Y89A-M1171, I43V-Y89A-M117L, I43V-Y89A-M117V, I43V-Y89A-M216A, I43V-Y89A-M216F, I43V-Y89A-M216L, I43V- Y89A-M117A-M216A, I43V-Y89A-M117A-M216F, I43V-Y89A-M117A-M216L, I43V-Y89A-M117F-M216A, I43V-Y89A-M117F-M216F, I43V-Y89A-M117F-M216L, I43V-Y89A-M117I-M216A, I43V-Y89A-M117I-M216F, I43V-Y89A-M117I-M216L, I43V-Y89A-M117L-M216A, I43V-Y89A-M117L-M216F, I43V-Y89A-M117L-M216L, I43V-Y89A-M117V-M216A, I43V-Y89A-M117V-M216F, I43V-Y89A-M117V-M216L, I43V-M117A, I43V-M117F, I43V-M1171, I43V-M117L, I43V-M117V, I43V-M117A-M216A, I43V-M117A-M216F, I43V-M117A-M216L, I43V-M117F-M216A, I43V-M117F-M216F, I43V-M117F-M216L, I43V-M117I-M216A, I43V-M117I-M216F, I43V-M117I-M216L, I43V-M117L-M216A, I43V-M117L-M216F, I43V-M117L-M216L, I43V-M117V-M216A, I43V-M117V-M216F, I43V-M117V-M216L, I43V-M216A, I43V-M216F, I43V-M216L, M122L-N154S-T156A-A29G, M122L-N154S-T156A-A29G-D58P, M122L-N154S-T156A-A29G-Y89A, M122L-N154S-T156A-A29G-M117A, M122L-N154S-T156A-A29G-M117F, M122L-N154S-T156A-A29G-M117I, M122L-N154S-T156A-A29G-M117L, M122L-N154S-T156A-A29G-M117V, M122L-N154S-T156A-A29G-M216A, M122L-N154S-T156A-A29G-M216F, M122L-N154S-T156A-A29G-M216L, M122L-N154S-T156A-A29G-D58P-Y89A, M122L-N154S-T156A-A29G-D58P-M117A, M122L-N154S-T156A-A29G-D58P-M117F, M122L-N154S-T156A-A29G-D58P-M117I, M122L-N154S-T156A-A29G-D58P-M117L, M122L-N154S-T156A-A29G-D58P-M117V, M122L-N154S-T156A-A29G-D58P-M216A, M122L-N154S-T156A-A29G-D58P-M216F, M122L-N154S-T156A-A29G-D58P-M216L, M122L-N154S-T156A-A29G-Y89A-M117A, M122L-N154S-T156A-A29G-Y89A-M117F, M122L-N154S-T156A-A29G-Y89A-M117I, M122L-N154S- T156A-A29G-Y89A-M117L, M122L-N154S-T156A-A29G-Y89A-M117V, M122L-N154S-T156A-A29G-Y89A-M216A, M122L-N154S-T156A-A29G-Y89A-M216F, M122L-N154S-T156A-A29G-Y89A-M216L, M122L-N154S-T156A-A29G-M117A-M216A, M122L-N154S-T156A-A29G-M117A-M216F, M122L- N154S-T156A-A29G-M117A-M216L, M122L-N154S-T156A-A29G-D58P-Y89A-M117A, M122L-N154S-T156A-A29G-D58P-Y89A-M117F, M122L-N154S-T156A-A29G-D58P-Y89A-M117I, M122L- N154S-T156A-A29G-D58P-Y89A-M117L, M122L-N154S-T156A-A29G-D58P-Y89A-M117V, M122L- N154S-T156A-A29G-D58P-Y89A-M216A, M122L-N154S-T156A-A29G-D58P-Y89A-M216F, M122L-N154S-T156A-A29G-D58P-Y89A-M216L, M122L-N154S-T156A-A29G-Y89A-M117A-M216A, M122L-N154S-T156A-A29G-Y89A-M117A-M216F, M122L-N154S-T156A-A29G-Y89A-M117A-M216L, M122L-N154S-T156A-A29G-Y89A-M117F-M216A, M122L-N154S-T156A-A29G-Y89A-M117F- M216F, M122L-N154S-T156A-A29G-Y89A-M117F-M216L, M122L-N154S-T156A-A29G-Y89A-M117I- M216A, M122L-N154S-T156A-A29G-Y89A-M117I-M216F, M122L-N154S-T156A-A29G-Y89A-M117I-M216L, M122L-N154S-T156A-A29G-Y89A-M117L-M216A, M122L-N154S-T156A-A29G-Y89A- M117L-M216F, M122L-N154S-T156A-A29G-Y89A-M117L-M216L, M122L-N154S-T156A-A29G- Y89A-M117V-M216A, M122L-N154S-T156A-A29G-Y89A-M117V-M216F, M122L-N154S-T156A- A29G-Y89A-M117V-M216L, M122L-N154S-T156A-D58P, 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M211 N-P212D-A29G-Y89A-M1171, M211 N-P212D-A29G-Y89A-M117L, M211 N-P212D-A29G-Y89A-M117V, M211 M211 N-P212D-A29G-M117A-M216F, M211 N-P212D-A29G-M117A-M216L, M211 N-P212D-A29G-D58P-Y89A-M117A, M211 N-P212D-A29G-D58P-Y89A-M117F, M211 N-P212D-A29G-D58P-Y89A-M117I, M211 N-P212D-A29G-D58P-Y89A-M117L, M211 N-P212D-A29G-D58P-Y89A-M117V, M211 N- P212D-A29G-D58P-Y89A-M216A, M211 N-P212D-A29G-D58P-Y89A-M216F, M211 N-P212D-A29G- D58P-Y89A-M216L, M211 N-P212D-A29G-Y89A-M117A-M216A, M211 N-P212D-A29G-Y89A-M117A-M216F, M211 N-P212D-A29G-Y89A-M117A-M216L, M211 N-P212D-A29G-Y89A-M117F-M216A, M211 N-P212D-A29G-Y89A-M117F-M216F, M211 N-P212D-A29G-Y89A-M117F-M216L, M211 N- P212D-A29G-Y89A-M117I-M216A, M211 N-P212D-A29— Y89A-M117I-M216F, M211 N-P212D-A29G- Y89A-M117I-M216L, M211 N-P212D-A29G-Y89A-M117L-M216A, M211 N-P212D-A29G-Y89A-M117L- M216F, M211 N-P212D-A29G-Y89A-M117L-M216L, M211 N-P212D-A29G-Y89A-M117V-M216A, M211 N-P212D-A29G-Y89A-M117V-M216F, M211 N-P212D-A29— Y89A-M117V-M216L, M211 N-P212D-D58P, M211 N-P212D-D58P-Y89A, M211 N-P212D-D58P-M117A, M211 N-P212D-D58P- M117F, M211 N-P212D-D58P-M117I, M211 M211 N-P212D-D58P-M216L, M211 P212D-D58P-Y89A-M117A, M211 N-P212D-D58P-Y89A-M117F, M211 N-P212D-D58P-Y89A-M117I, M211 N-P212D-D58P-Y89A-M117L, M211 M211 N-P212D-D58P-Y89A-M117V, M211 M211 M211 N-P212D-D58P-M117I-M216A N- P212D-D58P-M117I-M216L, M211 N-P212D-D58P-M117L-M216A, M211 N-P212D-D58P-M117L- M216F, M211 N-P212D-D58P-M117L-M216L, M211 N-P212D-D58P-M117V-M216A, M211 N-P212D- D58P-M117V-M216F, M211 N-P212D-D58P-M117V-M216L, M211 N-P212D-Y89A, M211 N-P212D Y89A-M117A, M211 N-P212D-Y89A-M117F, M211 N-P212D-Y89A-M1171, M211 N-P212D-Y89A-M117L, M211 N-P212D-Y89A-M117V, M211 N-P212D-Y89A-M216A, M211 N-P212D-Y89A-M216F, M211 N-P212D-Y89A-M216L, M211 N-P212D-Y89A-M117A-M216A, M211 N-P212D-Y89A-M117A- M216F, M211 M211 N-P212D-Y89A-M117F-M216L, M211 N-P212D-Y89A-M117I-M216A, M211 N-P212D-Y89A-M117I-M216F, M211 N-P212D-Y89A-M117I-M216L, M211 N-P212D-Y89A-M117L-M216A, M211 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D58P-Y89A-M216F, P212H-A29G-D58P-Y89A-M216L, P212H-A29G-Y89A-M117A-M216A, P212H- A29G-Y89A-M117A-M216F, P212H-A29G-Y89A-M117A-M216L, P212H-A29G-Y89A-M117F-M216A, P212H-A29G-Y89A-M117F-M216F, P212H-A29G-Y89A-M117F-M216L, P212H-A29G-Y89A-M1171-M216A, P212H-A29G-Y89A-M117I-M216F, P212H-A29G-Y89A-M117I-M216L, P212H-A29G-Y89A-M117L-M216A, P212H-A29G-Y89A-M117L-M216F, P212H-A29G-Y89A-M117L-M216L, P212H-A29G-Y89A-M117V-M216A, P212H-A29G-Y89A-M117V-M216F, P212H-A29G-Y89A-M117V-M216L, P212H-D58P, P212H-D58P-Y89A, P212H-D58P-M117A, P212H-D58P-M117F, P212H-D58P-M1171, P212H-D58P-M117L, P212H-D58P-M117V, P212H-D58P-M216A, P212H-D58P-M216F, P212H-D58P-M216L, P212H-D58P-Y89A-M117A, P212H-D58P-Y89A-M117F, P212H-D58P-Y89A-M117I, P212H-D58P-Y89A-M117L, P212H-D58P-Y89A-M117V, P212H-D58P-Y89A-M216A, P212H-D58P-Y89A-M216F, P212H-D58P-Y89A-M216L, P212H-D58P-M117A-M216A, P212H-D58P-M117A- M216F, P212H-D58P-M117A-M216L, P212H-D58P-M117F-M216A, P212H-D58P-M117F-M216F, P212H-D58P-M117F-M216L, P212H-D58P-M117I-M216A, P212H-D58P-M117I-M216F, P212H-D58P-M117I-M216L, P212H-D58P-M117L-M216A, P212H-D58P-M117L-M216F, P212H-D58P-M117L-M216L, P212H-D58P-M117V-M216A, P212H-D58P-M117V-M216F, P212H-D58P-M117V-M216L, P212H-Y89A, P212H-Y89A-M117A, P212H-Y89A-M117F, P212H-Y89A-M1171, P212H-Y89A-M117L, P212H-Y89A-M117V, P212H-Y89A-M216A, P212H-Y89A-M216F, P212H-Y89A-M216L, P212H-Y89A-M117A-M216A, P212H-Y89A-M117A-M216F, P212H-Y89A-M117A-M216L, P212H-Y89A-M117F-M216A, P212H-Y89A-M117F-M216F, P212H-Y89A-M117F-M216L, P212H-Y89A-M117I-M216A, P212H-Y89A-M117I-M216F, P212H-Y89A-M117I-M216L, P212H-Y89A-M117L-M216A, P212H-Y89A-M117L-M216F, P212H-Y89A-M117L-M216L, P212H-Y89A-M117V-M216A, P212H-Y89A-M117V-M216F, P212H-Y89A-M117V-M216L, P212H-M117A, P212H-M117F, P212H-M117I, P212H-M117L, P212H-M117V, P212H-M117A-M216A, P212H-M117A-M216F, P212H-M117A-M216L, P212H-M117F-M216A, P212H-M117F-M216F, P212H-M117F-M216L, P212H-M117I-M216A, P212H-M117I-M216F, P212H-M117I-M216L, P212H-M117L-M216A, P212H-M117L-M216F, P212H-M117L-M216L, P212H-M117V-M216A, P212H-M117V-M216F, P212H-M117V-M216L, P212H-M216A, P212H-M216F, P212H-M216L, Q12L-M122L-A222S-A29G, Q12L-M122L-A222S-A29G-D58P, Q12L-M122L-A222S-A29G-Y89A, Q12L-M122L-A222S-A29G-M117A, Q12L-M122L-A222S-A29G-M117F, Q12L-M122L-A222S-A29G-M1171, Q12L-M122L-A222S-A29G-M117L, Q12L-M122L-A222S-A29G-M117V, Q12L-M122L-A222S-A29G-M216A, Q12L-M122L-A222S-A29G-M216F, Q12L-M122L-A222S-A29G-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A, Q12L-M122L-A222S- A29G-D58P-M117A, Q12L-M122L-A222S-A29G-D58P-M117F, Q12L-M122L-A222S-A29G-D58P-M117I, Q12L-M122L-A222S-A29G-D58P-M117L, Q12L-M122L-A222S-A29G-D58P-M117V, Q12L- M122L-A222S-A29G-D58P-M216A, Q12L-M122L-A222S-A29G-D58P-M216F, Q12L-M122L-A222S- A29G-D58P-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A, Q12L-M122L-A222S-A29G-Y89A-M117F, Q12L-M122L-A222S-A29G-Y89A-M117I, Q12L-M122L-A222S-A29G-Y89A-M117L, Q12L- M122L-A222S-A29G-Y89A-M117V, Q12L-M122L-A222S-A29G-Y89A-M216A, Q12L-M122L-A222S- A29G-Y89A-M216F, Q12L-M122L-A222S-A29G-Y89A-M216L, Q12L-M122L-A222S-A29G-M117A-M216A, Q12L-M122L-A222S-A29G-M117A-M216F, Q12L-M122L-A222S-A29G-M117A-M216L, Q12L-M122L-A222S-A29G-D58P-Y89A-M117A, Q12L-M122L-A222S-A29G-D58P-Y89A-M117F, Q12L-M122L-A222S-A29G-D58P-Y89A-M117I , Q12L-M122L-A222S-A29G-D58P-Y89A-M117L, Q12L-M122L-A222S-A29G-D58P-Y89A-M216A, Q12L-M122L-A222S-A29G-D58P-Y89A-M216F, Q12L-M122L-A222S-A29G-D58P-Y89A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117A-M216A, Q12L-M122L-A222S-A29G-Y89A-M117A-M216F, Q12L-M122L-A222S-A29G-Y89A-M117A-M216L, Q12L-M122L-A222S-A29G-Y89A-M117F-M216A, Q12L-M122L-A222S-A29G-Y89A-M117F-M216F, Q12L-M122L-A222S-A29G-Y89A-M117F-M216L, Q12L-M122L-A222S-A29G-Y89A-M117I-M216A, Q12L-M122L-A222S-A29G-Y89A-M117I-M216F, Q12L-M122L-A222S-A29G-Y89A-M117I-M216L, Q12L-M122L-A222S-A29G-Y89A-M117L-M216A, Q12L-M122L-A222S-A29G-Y89A-M117L-M216F, Q12L-M122L-A222S-A29G-Y89A-M117L-M216L, Q12L-M122L-A222S-A29G-Y89A-M117V-M216A, Q12L-M122L-A222S-A29G-Y89A-M117V-M216F, Q12L-M122L-A222S-A29G-Y89A-M117V-M216L, Q12L-M122L-A222S-D58P, Q12L-M122L-A222S- D58P-Y89A, Q12L-M122L-A222S-D58P-M117A, Q12L-M122L-A222S-D58P-M117F, Q12L-M122L- A222S-D58P-M1171, Q12L-M122L-A222S-D58P-M117L, Q12L-M122L-A222S-D58P-M117V, Q12L-M122L-A222S-D58P-M216A, Q12L-M122L-A222S-D58P-M216F, Q12L-M122L-A222S-D58P-M216L, Q12L-M122L-A222S-D58P-Y89A-M117A, Q12L-M122L-A222S-D58P-Y89A-M117F, Q12L-M122L- A222S-D58P-Y89A-M1171, Q12L-M122L-A222S-D58P-Y89A-M117L, Q12L-M122L-A222S-D58P-Y89A-M117V, Q12L-M122L-A222S-D58P-Y89A-M216A, Q12L-M122L-A222S-D58P-Y89A-M216F, Q12L-M122L-A222S-D58P-Y89A-M216L, Q12L-M122L-A222S-D58P-M117A-M216A, Q12L-M122L- A222S-D58P-M117A-M216F, Q12L-M122L-A222S-D58P-M117A-M216L, Q12L-M122L-A222S-D58P-M117F-M216A, Q12L-M122L-A222S-D58P-M117F-M216F, Q12L-M122L-A222S-D58P-M117F-M216L, Q12L-M122L-A222S-D58P-M117I-M216A, Q12L-M122L-A222S-D58P-M117I-M216F, Q12L- M122L-A222S-D58P-M117I-M216L, Q12L-M122L-A222S-D58P-M117L-M216A, Q12L-M122L-A222S-D58P-M117L-M216F, Q12L-M122L-A222S-D58P-M117L-M216L, Q12L-M122L-A222S-D58P-M117V-M216A, Q12L-M122L-A222S-D58P-M117V-M216F, Q12L-M122L-A222S-D58P-M117V-M216L, Q12L-M122L-A222S-Y89A, Q12L-M122L-A222S-Y89A-M117A, Q12L-M122L-A222S-Y89A-M117F, Q12L-M122L-A222S-Y89A-M1171, Q12L-M122L-A222S-Y89A-M117L, Q12L-M122L-A222S-Y89A-M117V, Q12L-M122L-A222S-Y89A-M216A, Q12L-M122L-A222S-Y89A-M216F, Q12L-M122L-A222S-Y89A-M216L, Q12L-M122L-A222S-Y89A-M117A-M216A, Q12L-M122L-A222S-Y89A-M117A-M216F, Q12L-M122L-A222S-Y89A-M117A-M216L, Q12L-M122L-A222S-Y89A-M117F-M216A, Q12L-M122L- A222S-Y89A-M117F-M216F, Q12L-M122L-A222S-Y89A-M117F-M216L, Q12L-M122L-A222S-Y89A-M117I-M216A, Q12L-M122L-A222S-Y89A-M117I-M216F, Q12L-M122L-A222S-Y89A-M117I-M216L, Q12L-M122L-A222S-Y89A-M117L-M216A, Q12L-M122L-A222S-Y89A-M117L-M216F, Q12L-M122L- A222S-Y89A-M117L-M216L, Q12L-M122L-A222S-Y89A-M117V-M216A, Q12L-M122L-A222S-Y89A-M117V-M216F, Q12L-M122L-A222S-Y89A-M117V-M216L, Q12L-M122L-A222S-M117A, Q12L-M122L-A222S-M117F, Q12L-M122L-A222S-M1171, Q12L-M122L-A222S-M117L, Q12L-M122L- A222S-M117V, Q12L-M122L-A222S-M117A-M216A, Q12L-M122L-A222S-M117A-M216F, Q12L- M122L-A222S-M117A-M216L, Q12L-M122L-A222S-M117F-M216A, Q12L-M122L-A222S-M117F-M216F, Q12L-M122L-A222S-M117F-M216L, Q12L-M122L-A222S-M117I-M216A, Q12L-M122L-A222S-M117I-M216F, Q12L-M122L-A222S-M117I-M216L, Q12L-M122L-A222S-M117L-M216A, Q12L-M122L-A222S-M117L-M216F, Q12L-M122L-A222S-M117L-M216L, Q12L-M122L-A222S-M117V-M216A, Q12L-M122L-A222S-M117V-M216F, Q12L-M122L-A222S-M117V-M216L, Q12L-M122L-A222S-M216A, Q12L-M122L-A222S-M216F, Q12L-M122L-A222S-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO: 1, wherein the protease does not comprise any further changes besides the amino acid substitutions mentioned, and wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

In bevorzugten Ausführungsformen umfasst die erfindungsgemäße Protease eine M211 L-P212D- A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L- P212D-A29G-M117F, M211 L-P212D-A29G-M1171, M211 L-P212D-A29G-M117L, M211 L-P212D- A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G- M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G- D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D- A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L- P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A-M117L, M211 L-P212D-A29G-Y89A- M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D- A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D- A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A-M117I, M211 L-P212D-A29G-D58P- Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L-P212D- A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A-M216F, M211 L-P212D-A29G-Y89A- M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F- M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L-P212D-A29G-Y89A-M117I-M216A,In preferred embodiments, the protease according to the invention comprises a M211 L-P212D-A29G, M211 L-P212D-A29G-D58P, M211 L-P212D-A29G-Y89A, M211 L-P212D-A29G-M117A, M211 L-P212D-A29G-M117F, M211 L-P212D-A29G-M117I, M211 L-P212D-A29G-M117L, M211 L-P212D-A29G-M117V, M211 L-P212D-A29G-M216A, M211 L-P212D-A29G-M216F, M211 L-P212D-A29G- M216L, M211 L-P212D-A29G-D58P-Y89A, M211 L-P212D-A29G-D58P-M117A, M211 L-P212D-A29G- D58P-M117F, M211 L-P212D-A29G-D58P-M117I, M211 L-P212D-A29G-D58P-M117L, M211 L-P212D- A29G-D58P-M117V, M211 L-P212D-A29G-D58P-M216A, M211 L-P212D-A29G-D58P-M216F, M211 L-P212D-A29G-D58P-M216L, M211 L-P212D-A29G-Y89A-M117A, M211 L-P212D-A29G-Y89A-M117F, M211 L-P212D-A29G-Y89A-M117I, M211 L-P212D-A29G-Y89A-M117L, M211 L-P212D-A29G-Y89A-M117V, M211 L-P212D-A29G-Y89A-M216A, M211 L-P212D-A29G-Y89A-M216F, M211 L-P212D-A29G-Y89A-M216L, M211 L-P212D-A29G-M117A-M216A, M211 L-P212D-A29G-M117A-M216F, M211 L-P212D-A29G-M117A-M216L, M211 L-P212D-A29G-D58P-Y89A-M117A, M211 L-P212D- A29G-D58P-Y89A-M117F, M211 L-P212D-A29G-D58P-Y89A-M117I, M211 L-P212D-A29G-D58P-Y89A-M117L, M211 L-P212D-A29G-D58P-Y89A-M117V, M211 L-P212D-A29G-D58P-Y89A-M216A, M211 L-P212D-A29G-D58P-Y89A-M216F, M211 L-P212D-A29G-D58P-Y89A-M216L, M211 L-P212D- A29G-Y89A-M117A-M216A, M211 L-P212D-A29G-Y89A-M117A-M216F, M211 L-P212D-A29G-Y89A- M117A-M216L, M211 L-P212D-A29G-Y89A-M117F-M216A, M211 L-P212D-A29G-Y89A-M117F-M216F, M211 L-P212D-A29G-Y89A-M117F-M216L, M211 L-P212D-A29G-Y89A-M117I-M216A,

M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D- A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A- M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V- M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P- Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L- P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L-P212D-D58P-Y89A-M117A, M211 L- P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M117I, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L-P212D-D58P-Y89A- M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D- D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P- M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L-P212D-D58P-M117I-M216L, M211 L- P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L- M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D- D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D-Y89A-M117A, M211 L-P212D-Y89A- M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L- P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A-M216F, M211 L-P212D-Y89A-M117A- M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D- Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A- M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L- P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V-M216L, M211 L-P212D-M117A, M211 L- P212D-M117F, M211 L-P212D-M1171, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D- M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F- M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L- P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D- M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L bestehenden Gruppe ausgewählt ist, wobei die Nummerierung jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 ist, wobei die Protease neben den genannten Aminosäuresubstitutionen keine weiteren Änderungen umfasst, und wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. M211 L-P212D-A29G-Y89A-M117I-M216F, M211 L-P212D-A29G-Y89A-M117I-M216L, M211 L-P212D- A29G-Y89A-M117L-M216A, M211 L-P212D-A29G-Y89A-M117L-M216F, M211 L-P212D-A29G-Y89A- M117L-M216L, M211 L-P212D-A29G-Y89A-M117V-M216A, M211 L-P212D-A29G-Y89A-M117V- M216F, M211 L-P212D-A29G-Y89A-M117V-M216L, M211 L-P212D-D58P, M211 L-P212D-D58P-Y89A, M211 L-P212D-D58P-M117A, M211 L-P212D-D58P-M117F, M211 L-P212D-D58P-M117I, M211 L-P212D-D58P-M117L, M211 L-P212D-D58P-M117V, M211 L-P212D-D58P-M216A, M211 L-P212D-D58P-M216F, M211 L-P212D-D58P-M216L, M211 L-P212D-D58P-Y89A-M117A, M211 L-P212D-D58P-Y89A-M117F, M211 L-P212D-D58P-Y89A-M117I, M211 L-P212D-D58P-Y89A-M117L, M211 L-P212D-D58P-Y89A-M117V, M211 L-P212D-D58P-Y89A-M216A, M211 L-P212D-D58P-Y89A- M216F, M211 L-P212D-D58P-Y89A-M216L, M211 L-P212D-D58P-M117A-M216A, M211 L-P212D-D58P-M117A-M216F, M211 L-P212D-D58P-M117A-M216L, M211 L-P212D-D58P-M117F-M216A, M211 L-P212D-D58P-M117F-M216F, M211 L-P212D-D58P-M117F-M216L, M211 L-P212D-D58P-M117I-M216A, M211 L-P212D-D58P-M117I-M216F, M211 L-P212D-D58P-M117I-M216L, M211 L-P212D-D58P-M117L-M216A, M211 L-P212D-D58P-M117L-M216F, M211 L-P212D-D58P-M117L- M216L, M211 L-P212D-D58P-M117V-M216A, M211 L-P212D-D58P-M117V-M216F, M211 L-P212D-D58P-M117V-M216L, M211 L-P212D-Y89A, M211 L-P212D-Y89A-M117A, M211 L-P212D-Y89A- M117F, M211 L-P212D-Y89A-M1171, M211 L-P212D-Y89A-M117L, M211 L-P212D-Y89A-M117V, M211 L-P212D-Y89A-M216A, M211 L-P212D-Y89A-M216F, M211 L-P212D-Y89A-M216L, M211 L-P212D-Y89A-M117A-M216A, M211 L-P212D-Y89A-M117A-M216F, M211 L-P212D-Y89A-M117A-M216L, M211 L-P212D-Y89A-M117F-M216A, M211 L-P212D-Y89A-M117F-M216F, M211 L-P212D-Y89A-M117F-M216L, M211 L-P212D-Y89A-M117I-M216A, M211 L-P212D-Y89A-M117I-M216F, M211 L-P212D-Y89A-M117I-M216L, M211 L-P212D-Y89A-M117L-M216A, M211 L-P212D-Y89A- M117L-M216F, M211 L-P212D-Y89A-M117L-M216L, M211 L-P212D-Y89A-M117V-M216A, M211 L-P212D-Y89A-M117V-M216F, M211 L-P212D-Y89A-M117V-M216L, M211 L-P212D-M117A, M211 L-P212D-M117F, M211 L-P212D-M1171, M211 L-P212D-M117L, M211 L-P212D-M117V, M211 L-P212D-M117A-M216A, M211 L-P212D-M117A-M216F, M211 L-P212D-M117A-M216L, M211 L-P212D-M117F-M216A, M211 L-P212D-M117F-M216F, M211 L-P212D-M117F-M216L, M211 L-P212D-M117I-M216A, M211 L-P212D-M117I-M216F, M211 L-P212D-M117I-M216L, M211 L-P212D-M117L-M216A, M211 L- P212D-M117L-M216F, M211 L-P212D-M117L-M216L, M211 L-P212D-M117V-M216A, M211 L-P212D- M117V-M216F, M211 L-P212D-M117V-M216L, M211 L-P212D-M216A, M211 L-P212D-M216F, M211 L-P212D-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO:1, wherein the protease comprises no further changes besides the amino acid substitutions mentioned, and wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, wherein the stability is determined as described in Example 3.

In bevorzugten Ausführungsformen umfasst die erfindungsgemäße Protease eine Aminosäuresubstitutionskombination, die aus der aus M117A-M211 L-P212D, Y89A-M117A-M211 L- P212D, M117V-M211 L-P212D, A29G-M117V-M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L- P212D, M117L-M211 L-P212D, M211 L-P212D-M216F, D58P-M211 L-P212D-M216A und M211 L- P212D-M216L bestehenden Gruppe ausgewählt ist, wobei die Nummerierung jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 ist, wobei die Protease neben den genannten Aminosäuresubstitutionen keine weiteren Änderungen umfasst, und wobei die Protease eine verbesserte Stabilität in Gegenwart von Bleichmitteln, insbesondere Oxidationsmitteln, aufweist, wobei die Stabilität wie in Beispiel 3 beschrieben bestimmt wird. In preferred embodiments, the protease according to the invention comprises an amino acid substitution combination selected from the group consisting of M117A-M211 L-P212D, Y89A-M117A-M211 L-P212D, M117V-M211 L-P212D, A29G-M117V-M211 L-P212D, M117F-M211 L-P212D, M117I-M211 L-P212D, M117L-M211 L-P212D, M211 L-P212D-M216F, D58P-M211 L-P212D-M216A and M211 L-P212D-M216L, wherein the numbering is in each case based on the numbering according to SEQ ID NO:1, wherein the Protease comprises no further changes besides the amino acid substitutions mentioned, and wherein the protease has improved stability in the presence of bleaching agents, in particular oxidizing agents, the stability being determined as described in Example 3.

Erfindungsgemäße Proteasen verfügen über eine erhöhte katalytische Aktivität in Wasch- und Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugte bleichmittelhaltigen Maschinengeschirrspülmitteln. In vielfältigen Ausführungsformen können die erfindungsgemäßen Proteasen eine proteolytische Aktivität besitzen, die bezogen auf den Wildtyp (SEQ ID NO:1) mindestens 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130% oder mehr beträgt. Solche leistungsverbesserten Proteasen ermöglichen verbesserte Reinigungsergebnisse an proteasesensitiven Anschmutzungen. Solche leistungsverbesserten Reinigungsergebnisse an proteasesensitiven Anschmutzungen können in verschiedenen Temperaturbereichen erzielt werden, z.B. in einem Bereich von etwa 0°C bis etwa 100°C, bevorzugt etwa 20°C bis etwa 75°C, weiter bevorzugt etwa 30°C bis etwa 60°C, besonders bevorzugt etwa 40°C bis etwa 55°C. Proteases according to the invention have increased catalytic activity in washing and cleaning agents, in particular washing and cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach. In various embodiments, the proteases according to the invention can have a proteolytic activity of at least 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, or more, based on the wild type (SEQ ID NO:1). Such performance-enhanced proteases enable improved cleaning results on protease-sensitive soils. Such performance-improved cleaning results on protease-sensitive soils can be achieved in various temperature ranges, e.g. in a range from about 0°C to about 100°C, preferably about 20°C to about 75°C, more preferably about 30°C to about 60°C, particularly preferably about 40°C to about 55°C.

Die erfindungsgemäßen Proteasen verfügen über eine hohe Stabilität in Wasch- und Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- und Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugte bleichmittelhaltigen Maschinengeschirrspülmitteln. In bevorzugten Ausführungsformen verfügen erfindungsgemäße Proteasen zudem über eine hohe Stabilität z.B. gegenüber Tensiden und/oder Chelatoren, und/oder gegenüber Temperatureinflüssen, insbesondere gegenüber hohen Temperaturen, z.B. zwischen etwa 50°C und etwa 65°C, insbesondere etwa 60°C, und/oder gegenüber sauren oder alkalischen Bedingungen und/oder gegenüber pH-Wert-Änderungen und/oder gegenüber denaturierenden oder oxidierenden Agentien und/oder gegenüber (auto)proteolytischem Abbau und/oder gegenüber einer Veränderung der Redox-Verhältnisse. The proteases according to the invention have high stability in detergents and cleaning agents, in particular detergents and cleaning agents containing bleach, preferably automatic dishwashing detergents, particularly preferably automatic dishwashing detergents containing bleach. In preferred embodiments, proteases according to the invention also have high stability, e.g., towards surfactants and/or chelators, and/or towards temperature influences, in particular towards high temperatures, e.g., between about 50°C and about 65°C, in particular about 60°C, and/or towards acidic or alkaline conditions and/or towards pH changes and/or towards denaturing or oxidizing agents and/or towards (auto)proteolytic degradation and/or towards a change in redox ratios.

Die erfindungsgemäßen Proteasen weisen enzymatische Aktivität auf, d.h. sie sind zur Hydrolyse von Peptiden und Proteinen befähigt, insbesondere in Wasch- und Reinigungsmitteln. Eine erfindungsgemäße Protease ist daher ein Enzym, welches die Hydrolyse von Amid/Peptidbindungen in Protein/Peptid-Substraten katalysiert und dadurch in der Lage ist, Proteine oder Peptide zu spalten. The proteases according to the invention have enzymatic activity, ie they are capable of hydrolyzing peptides and proteins, particularly in washing and cleaning agents. The protease according to the invention is therefore an enzyme which catalyzes the hydrolysis of amide/peptide bonds in protein/peptide substrates and is thus able to cleave proteins or peptides.

Ferner handelt es sich bei einer erfindungsgemäßen Protease vorzugsweise um eine reife (mature) Protease, d.h. um das katalytisch aktive Molekül ohne Signal- und/oder Propeptid(e). Soweit nicht anders angegeben beziehen sich auch die angegebenen Sequenzen auf jeweils reife (prozessierte) Enzyme. Furthermore, a protease according to the invention is preferably a mature protease, i.e., the catalytically active molecule without signal and/or propeptide(s). Unless otherwise stated, the sequences indicated also refer to mature (processed) enzymes.

In verschiedenen Ausführungsformen der Erfindung ist die Protease ein frei vorliegendes Enzym. Dies bedeutet, dass die Protease mit allen Komponenten eines Mittels direkt agieren kann und, falls es sich bei dem Mittel um ein Flüssigmittel handelt, dass die Protease direkt mit dem Lösungsmittel des Mittels (z.B. Wasser) in Kontakt steht. In anderen Ausführungsformen kann ein Mittel Proteasen enthalten, die einen Interaktionskomplex mit anderen Molekülen bilden oder die eine "Umhüllung" enthalten. Hierbei kann ein einzelnes oder mehrere Protease-Molekül(e) durch eine sie umgebende Struktur von den anderen Bestandteilen des Mittels getrennt sein. Eine solche trennende Struktur kann entstehen durch, ist allerdings nicht beschränkt auf, Vesikel, wie etwa eine Micelle oder ein Liposom. Die umgebende Struktur kann aber auch ein Viruspartikel, eine bakterielle Zelle oder eine eukaryotische Zelle sein. In verschiedenen Ausführungsformen kann ein Mittel Zellen von z.B. Bacillus pumilus oder Bacillus subtilis oder anderen Expressionsstämmen, die die erfindungsgemäßen Proteasen exprimieren, oder Zellkulturüberstände solcher Zellen enthalten. In various embodiments of the invention, the protease is a free enzyme. This means that the protease can interact directly with all components of a composition and, if the composition is a liquid composition, that the protease is in direct contact with the composition's solvent (e.g., water). In other embodiments, a composition may contain proteases that form an interaction complex with other molecules or that contain a "coat." In this case, a single or multiple protease molecules may be separated from the other components of the composition by a surrounding structure. Such a separating structure may be formed by, but is not limited to, vesicles, such as a micelle or a liposome. However, the surrounding structure may also be a virus particle, a bacterial cell, or a eukaryotic cell. In various embodiments, an agent may contain cells of, for example, Bacillus pumilus or Bacillus subtilis or other expression strains expressing the proteases of the invention, or cell culture supernatants of such cells.

Die Bestimmung der Identität von Nukleinsäure- oder Aminosäuresequenzen erfolgt durch einen Sequenzvergleich. Dieser Sequenzvergleich basiert auf dem im Stand der Technik etablierten und üblicherweise genutzten BLAST-Algorithmus (vgl. z.B. Altschul et al., Basic local alignment search tool, J. Mol. Biol., 1990, 215:403-410, und Altschul et al., Gapped BLAST and PSI-BLAST: a new generation of protein database search programs, Nucleic Acids Res., 1997, 25:3389-3402) und geschieht prinzipiell dadurch, dass ähnliche Abfolgen von Nukleotiden oder Aminosäuren in den Nukleinsäure- oder Aminosäuresequenzen einander zugeordnet werden. Eine tabellarische Zuordnung der betreffenden Positionen wird als Alignment bezeichnet. Ein weiterer im Stand der Technik verfügbarer Algorithmus ist der FASTA-Algorithmus. Sequenzvergleiche (Alignments), insbesondere multiple Sequenzvergleiche, werden mit Computerprogrammen erstellt. Häufig genutzt werden z.B. die Clustal-Serie (vgl. z.B. Chenna et al., Multiple sequence alignment with the Clustal series of programs, Nucleic Acid Res., 2003, 31 :3497-3500), T-Coffee (vgl. Z.B. Notredame et al., T- Coffee: A novel method for multiple sequence alignments, J. Mol. Biol., 2000, 302:205-217) oder Programme, die auf diesen Programmen bzw. Algorithmen basieren. Ferner möglich sind Sequenzvergleiche (Alignments) mit dem Computer-Programm Vector NTI® Suite 10.3 (Invitrogen Corporation, 1600 Faraday Avenue, Carlsbad, Kalifornien, USA) mit den vorgegebenen Standardparametern, dessen AlignX-Modul für die Sequenzvergleiche auf ClustalW basiert, oder Clone Manager 10 (Verwendung der Scoring Matrix BLOSUM 62 für Sequenz-Alignment auf Aminosäureebene). Soweit nicht anders angegeben, wird die hierin angegebene Sequenzidentität mit dem BLAST-Algorithmus bestimmt. The identity of nucleic acid or amino acid sequences is determined by sequence comparison. This sequence comparison is based on the BLAST algorithm, which is established and commonly used in the state of the art (see, for example, Altschul et al., Basic local alignment search tool, J. Mol. Biol., 1990, 215:403-410, and Altschul et al., Gapped BLAST and PSI-BLAST: a new generation of protein database search programs, Nucleic Acids Res., 1997, 25:3389-3402) and is essentially performed by matching similar sequences of nucleotides or amino acids in the nucleic acid or amino acid sequences. A tabular assignment of the relevant positions is referred to as an alignment. Another algorithm available in the state of the art is the FASTA algorithm. Sequence comparisons (alignments), especially multiple sequence comparisons, are created using computer programs. Frequently used programs are, for example, the Clustal series (see, for example, Chenna et al., Multiple sequence alignment with the Clustal series of programs, Nucleic Acid Res., 2003, 31:3497-3500), T-Coffee (see, for example, Notredame et al., T-Coffee: A novel method for multiple sequence alignments, J. Mol. Biol., 2000, 302:205-217) or programs based on these programs or algorithms. Sequence comparisons (alignments) are also possible using the computer program Vector NTI® Suite 10.3 (Invitrogen Corporation, 1600 Faraday Avenue, Carlsbad, California, USA) with the specified default parameters. Its AlignX module for sequence comparisons is based on ClustalW. Clone Manager 10 (using the BLOSUM 62 scoring matrix for sequence alignment at the amino acid level) or Clone Manager 10 (using the BLOSUM 62 scoring matrix for sequence alignment at the amino acid level) are also possible. Unless otherwise stated, the sequence identity stated herein is determined using the BLAST algorithm.

Solch ein Vergleich erlaubt auch eine Aussage über die Ähnlichkeit der verglichenen Sequenzen zueinander. Sie wird üblicherweise in Prozent Identität, das heißt dem Anteil der identischen Nukleotide oder Aminosäurereste an denselben oder in einem Alignment einander entsprechenden Positionen angegeben. Der weiter gefasste Begriff der Homologie bezieht bei Aminosäuresequenzen konservierte Aminosäure-Austausche in die Betrachtung mit ein, also Aminosäuren mit ähnlicher chemischer Aktivität, da diese innerhalb des Proteins meist ähnliche chemische Aktivitäten ausüben. Daher kann die Ähnlichkeit der verglichenen Sequenzen auch Prozent Homologie oder Prozent Ähnlichkeit angegeben sein. Identitäts- und/oder Homologieangaben können über ganze Polypeptide oder Gene oder nur über einzelne Bereiche getroffen werden. Homologe oder identische Bereiche von verschiedenen Nukleinsäure- oder Aminosäuresequenzen sind daher durch Übereinstimmungen in den Sequenzen definiert. Solche Bereiche weisen oftmals identische Funktionen auf. Sie können klein sein und nur wenige Nukleotide oder Aminosäuren umfassen. Oftmals üben solche kleinen Bereiche für die Gesamtaktivität des Proteins essenzielle Funktionen aus. Es kann daher sinnvoll sein, Sequenzübereinstimmungen nur auf einzelne, ggf. kleine Bereiche zu beziehen. Soweit nicht anders angegeben beziehen sich Identitäts- oder Homologieangaben in der vorliegenden Anmeldung aber auf die Gesamtlänge der jeweils angegebenen Nukleinsäure- oder Aminosäuresäuresequenz. Such a comparison also allows a statement about the similarity of the compared sequences. This is usually expressed as percent identity, i.e. the proportion of identical Nucleotides or amino acid residues at the same or corresponding positions in an alignment are specified. The broader term homology in amino acid sequences includes conserved amino acid substitutions, i.e. amino acids with similar chemical activity, since these usually exert similar chemical activities within the protein. Therefore, the similarity of the compared sequences can also be specified as percent homology or percent similarity. Identity and/or homology statements can be made for entire polypeptides or genes or just for individual regions. Homologous or identical regions of different nucleic acid or amino acid sequences are therefore defined by similarities in the sequences. Such regions often have identical functions. They can be small and consist of only a few nucleotides or amino acids. Such small regions often exert essential functions for the overall activity of the protein. It can therefore be useful to relate sequence similarities only to individual, possibly small regions. Unless otherwise stated, details of identity or homology in the present application refer to the total length of the respective nucleic acid or amino acid sequence indicated.

Im Zusammenhang mit der vorliegenden Erfindung bedeutet die Angabe, dass eine Aminosäureposition einer numerisch bezeichneten Position in SEQ ID NO:1 entspricht daher, dass die entsprechende Position der numerisch bezeichneten Position in SEQ ID NO:1 in einem wie oben definierten Alignment zugeordnet ist. Weiterhin richtet sich die Zuordnung der Positionen nach dem reifen (maturen) Protein. Diese Zuordnung ist insbesondere auch anzuwenden, wenn die Aminosäuresequenz einer erfindungsgemäßen Protease eine höhere Zahl von Aminosäureresten umfasst als die Protease gemäß SEQ ID NO:1 . Ausgehend von den genannten Positionen in der Aminosäuresequenz der Protease gemäß SEQ ID NO:1 sind die Veränderungspositionen in einer erfindungsgemäßen Protease diejenigen, die eben diesen Positionen in einem Alignment zugeordnet sind. In the context of the present invention, the statement that an amino acid position corresponds to a numerically designated position in SEQ ID NO:1 therefore means that the corresponding position is assigned to the numerically designated position in SEQ ID NO:1 in an alignment as defined above. Furthermore, the assignment of the positions is based on the mature protein. This assignment is also to be applied in particular if the amino acid sequence of a protease according to the invention comprises a higher number of amino acid residues than the protease according to SEQ ID NO:1. Starting from the stated positions in the amino acid sequence of the protease according to SEQ ID NO:1, the change positions in a protease according to the invention are those that are assigned to precisely these positions in an alignment.

Zusätzlich zu den vorstehend erläuterten Aminosäureveränderungen können erfindungsgemäße Proteasen weitere Aminosäureveränderungen, insbesondere Aminosäure-Substitutionen, -Insertionen oder -Deletionen, aufweisen. Solche Proteasen sind z.B. durch gezielte genetische Veränderung, d.h. durch Mutageneseverfahren, weiterentwickelt und für bestimmte Einsatzzwecke oder hinsichtlich spezieller Eigenschaften (z.B. hinsichtlich ihrer katalytischen Aktivität, Stabilität, usw.) optimiert. Ferner können erfindungsgemäße Nukleinsäuren in Rekombinationsansätze eingebracht und damit zur Erzeugung völlig neuartiger Proteasen oder anderer Polypeptide genutzt werden. Das Ziel ist es, in die bekannten Moleküle gezielte Mutationen wie Substitutionen, Insertionen oder Deletionen einzuführen, um z.B. die Reinigungsleistung von erfindungsgemäßen Enzymen zu verbessern. Hierzu können insbesondere die Oberflächenladungen und/oder der isoelektrische Punkt der Moleküle und dadurch ihre Wechselwirkungen mit dem Substrat verändert werden. So kann z.B. die Nettoladung der Enzyme verändert werden, um darüber die Substratbindung insbesondere für den Einsatz in Wasch- und Reinigungsmitteln zu beeinflussen. Alternativ oder ergänzend kann durch eine oder mehrere entsprechende Mutationen die Stabilität oder katalytische Aktivität der Protease erhöht und dadurch ihre Reinigungsleistung verbessert werden. Vorteilhafte Eigenschaften einzelner Mutationen, z.B. einzelner Substitutionen, können sich ergänzen. Eine hinsichtlich bestimmter Eigenschaften bereits optimierte Protease, z.B. hinsichtlich ihrer Stabilität bei Lagerung und/oder Aktivität und/oder ihrer Toleranz in Bezug auf das Substratspektrum, kann daher im Rahmen der Erfindung zusätzlich weiterentwickelt sein. In addition to the amino acid modifications explained above, proteases according to the invention can have further amino acid modifications, in particular amino acid substitutions, insertions or deletions. Such proteases are further developed, for example, by targeted genetic modification, i.e., by mutagenesis methods, and optimized for specific applications or with regard to special properties (e.g., with regard to their catalytic activity, stability, etc.). Furthermore, nucleic acids according to the invention can be introduced into recombination approaches and thus used to generate completely new types of proteases or other polypeptides. The aim is to introduce targeted mutations such as substitutions, insertions or deletions into the known molecules in order, for example, to improve the cleaning performance of enzymes according to the invention. For this purpose, in particular the surface charges and/or the isoelectric point of the molecules and thus their interactions with the substrate can be modified. For example, the net charge of the enzymes can be modified in order to influence substrate binding, particularly for use in detergents and cleaning agents. Alternatively or additionally, one or more corresponding mutations can increase the stability or catalytic activity of the protease and thereby improve its purification performance. Advantageous properties of individual mutations, e.g., individual substitutions, can complement each other. A protease that has already been optimized with regard to certain properties, e.g., with regard to its stability during storage and/or activity and/or their tolerance with respect to the substrate spectrum, can therefore be further developed within the scope of the invention.

Für die Beschreibung von Substitutionen, die genau eine Aminosäureposition betreffen (Aminosäureaustausche), wird hierin folgende Konvention angewendet: zunächst wird die natürlicherweise vorhandene Aminosäure in Form des international gebräuchlichen Einbuchstaben- Codes bezeichnet, dann folgt die zugehörige Sequenzposition und schließlich die eingefügte Aminosäure. Mehrere oder alternative Austausche innerhalb derselben Polypeptidkette werden durch Schrägstriche voneinander getrennt. "130D/V" bedeutet somit, dass die Position 130 zu D oder V mutiert ist. Bei Insertionen sind nach der Sequenzposition zusätzliche Aminosäuren benannt. Bei Deletionen ist die fehlende Aminosäure durch ein Symbol, z.B. einen Stern oder einen Strich, ersetzt oder vor der entsprechenden Position ein A angegeben. Beispielsweise beschreibt P9T die Substitution von Prolin an Position 9 durch Threonin, P9TH die Insertion von Histidin nach der Aminosäure Threonin an Position 9 und P9* oder AP9 die Deletion von Prolin an Position 9. Diese Nomenklatur ist dem Fachmann auf dem Gebiet der Enzymtechnologie bekannt. The following convention is used to describe substitutions that affect exactly one amino acid position (amino acid exchanges): first, the naturally occurring amino acid is designated using the internationally accepted one-letter code, followed by the corresponding sequence position, and finally, the inserted amino acid. Multiple or alternative exchanges within the same polypeptide chain are separated by slashes. "130D/V" thus means that position 130 is mutated to D or V. In the case of insertions, additional amino acids are named after the sequence position. In the case of deletions, the missing amino acid is replaced by a symbol, e.g., an asterisk or a dash, or an A is indicated before the corresponding position. For example, P9T describes the substitution of proline at position 9 with threonine, P9TH the insertion of histidine after the amino acid threonine at position 9, and P9* or AP9 the deletion of proline at position 9. This nomenclature is familiar to those skilled in the art of enzyme technology.

Ein weiterer Gegenstand der Erfindung ist daher eine Protease, die dadurch gekennzeichnet ist, dass sie aus einer Protease wie hierin beschrieben als Ausgangsmolekül erhältlich ist durch ein- oder mehrfache konservative Aminosäuresubstitution, wobei die Protease in der Zählung gemäß SEQ ID NO:1 mindestens eine der vorstehend beschriebenen Aminosäuresubstitutionen aufweist. Der Begriff "konservative Aminosäuresubstitution" bedeutet den Austausch (Substitution) eines Aminosäurerestes gegen einen anderen Aminosäurerest, wobei dieser Austausch nicht zu einer Änderung der Polarität oder Ladung an der Position der ausgetauschten Aminosäure führt, z.B. der Austausch eines unpolaren Aminosäurerestes gegen einen anderen unpolaren Aminosäurerest. Konservative Aminosäuresubstitutionen im Rahmen der Erfindung umfassen z.B.: G=A=S, l=V=L=M, D=E, N=Q, K=R, Y=F, S=T, G=A=I=V=L=M=Y=F=W=P=S=T. The invention therefore further provides a protease which is characterized in that it is obtainable from a protease as described herein as the starting molecule by single or multiple conservative amino acid substitution, wherein the protease has at least one of the amino acid substitutions described above in the numbering according to SEQ ID NO: 1. The term "conservative amino acid substitution" means the exchange (substitution) of one amino acid residue for another amino acid residue, wherein this exchange does not lead to a change in the polarity or charge at the position of the exchanged amino acid, e.g., the exchange of one non-polar amino acid residue for another non-polar amino acid residue. Conservative amino acid substitutions within the scope of the invention include, for example: G=A=S, I=V=L=M, D=E, N=Q, K=R, Y=F, S=T, G=A=I=V=L=M=Y=F=W=P=S=T.

Alternativ oder ergänzend ist die Protease dadurch gekennzeichnet, dass sie aus einer erfindungsgemäßen Protease als Ausgangsmolekül erhältlich ist durch Fragmentierung, Deletions-, Insertions- oder Substitutionsmutagenese und eine Aminosäuresequenz umfasst, die über eine Länge von mindestens 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261 , 262, 263, 264, 265, 266, 267, 268 oder 269 zusammenhängenden Aminosäuren mit dem Ausgangsmolekül übereinstimmt, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. Alternatively or additionally, the protease is characterized in that it is obtainable from a protease according to the invention as starting molecule by fragmentation, deletion, insertion or substitution mutagenesis and comprises an amino acid sequence which corresponds to the starting molecule over a length of at least 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268 or 269 contiguous amino acids, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

So ist es z.B. möglich, an den Termini oder in den Loops des Enzyms einzelne Aminosäuren zu deletieren, ohne dass dadurch die proteolytische Aktivität verloren oder vermindert wird. Ferner kann durch derartige Fragmentierung, Deletions-, Insertions- oder Substitutionsmutagenese z.B. auch die Allergenizität betreffender Enzyme gesenkt und somit insgesamt ihre Einsetzbarkeit verbessert werden. Vorteilhafterweise behalten die Enzyme auch nach der Mutagenese ihre proteolytische Aktivität, d.h. ihre proteolytische Aktivität entspricht mindestens derjenigen des Ausgangsenzyms, d.h. in einer bevorzugten Ausführungsform beträgt die proteolytische Aktivität mindestens 100%, vorzugsweise mindestens 105%, weiter bevorzugt mindestens 110%, noch weiter bevorzugt mindestens 120% oder mehr, der Aktivität des Ausgangsenzyms. Auch weitere Substitutionen können vorteilhafte Wirkungen zeigen. Sowohl einzelne wie auch mehrere zusammenhängende Aminosäuren können gegen andere Aminosäuren ausgetauscht werden. For example, it is possible to delete individual amino acids at the termini or in the loops of the enzyme without losing or reducing the proteolytic activity. Furthermore, such fragmentation, deletion, insertion, or substitution mutagenesis can also The allergenicity of relevant enzymes can be reduced and their usability improved overall. Advantageously, the enzymes retain their proteolytic activity even after mutagenesis, i.e., their proteolytic activity corresponds at least to that of the starting enzyme, i.e., in a preferred embodiment, the proteolytic activity is at least 100%, preferably at least 105%, more preferably at least 110%, even more preferably at least 120% or more, of the activity of the starting enzyme. Other substitutions can also have advantageous effects. Both individual amino acids and multiple contiguous amino acids can be exchanged for other amino acids.

Vorteilhafte Positionen für Sequenzveränderungen, insbesondere Substitutionen, der Protease gemäß SEQ ID NO:1 , die übertragen auf homologe Positionen der erfindungsgemäßen Proteasen bevorzugt von Bedeutung sind und der Protease vorteilhafte funktionelle Eigenschaften verleihen, sind demnach die Positionen, die in einem Alignment den hierin beschriebenen Positionen entsprechen, d.h. in der Zählung gemäß SEQ ID NO:1 . An den genannten Positionen liegen in dem Wildtypmolekül der Protease folgende Aminosäurereste: 29A, 58D, 89Y, 117M, 216M. Advantageous positions for sequence changes, in particular substitutions, of the protease according to SEQ ID NO:1, which, when transferred to homologous positions of the proteases according to the invention, are preferably of importance and impart advantageous functional properties to the protease, are therefore the positions which, in an alignment, correspond to the positions described herein, i.e., in the numbering according to SEQ ID NO:1. The following amino acid residues are located at the stated positions in the wild-type molecule of the protease: 29A, 58D, 89Y, 117M, 216M.

Eine weitere Bestätigung der korrekten Zuordnung der zu verändernden Aminosäuren, d.h. insbesondere deren funktionelle Entsprechung, können Vergleichsversuche liefern, wonach die beiden auf der Basis eines Alignments einander zugeordneten Positionen in beiden miteinander verglichenen Proteasen auf die gleiche Weise verändert werden und beobachtet wird, ob bei beiden die enzymatische Aktivität auf gleiche Weise verändert wird. Geht z.B. ein Aminosäureaustausch in einer bestimmten Position der Protease gemäß SEQ ID NO:1 mit einer Veränderung eines enzymatischen Parameters einher, z.B. mit der Erhöhung des KM-Wertes, und wird eine entsprechende Veränderung des enzymatischen Parameters, z.B. also ebenfalls eine Erhöhung des KM-Wertes, in einer erfindungsgemäßen Protease-Variante beobachtet, deren Aminosäureaustausch durch dieselbe eingeführte Aminosäure erreicht wurde, so ist hierin eine Bestätigung der korrekten Zuordnung zu sehen. Further confirmation of the correct assignment of the amino acids to be modified, i.e., in particular their functional correspondence, can be provided by comparative experiments, according to which the two positions assigned to each other on the basis of an alignment are modified in the same way in both compared proteases, and it is observed whether the enzymatic activity is changed in the same way in both. For example, if an amino acid exchange in a specific position of the protease according to SEQ ID NO:1 is accompanied by a change in an enzymatic parameter, e.g., an increase in the KM value, and a corresponding change in the enzymatic parameter, e.g., also an increase in the KM value, is observed in a protease variant according to the invention whose amino acid exchange was achieved by the same introduced amino acid, this is to be seen as confirmation of the correct assignment.

Alle genannten Sachverhalte sind auch auf die erfindungsgemäßen Verfahren zur Herstellung einer Protease anwendbar. All of the above-mentioned facts are also applicable to the processes according to the invention for producing a protease.

Ein erfindungsgemäßes Verfahren zur Herstellung einer Protease, umfasst das Einbringen (i) mindestens einer Aminosäuresubstitution an mindestens einer der Positionen, die bezogen auf die Nummerierung gemäß SEQ ID NO:1 den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, ausgewählt aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe, und (ii) mindestens einer Aminosäuresubstitution an mindestens einer der Positionen, die bezogen auf die Nummerierung gemäß SEQ ID NO:1 den Positionen 29, 58, 89, 117 und 216 entsprechen, ausgewählt aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe, in ein Ausgangsmolekül, das eine Aminosäuresequenz aufweist, die mindestens 70% und zunehmend bevorzugt zu mindestens 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91%, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5%, 99%, 99,5% oder 100% Sequenzidentität mit der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge aufweist. A process according to the invention for producing a protease comprises introducing (i) at least one amino acid substitution at at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, based on the numbering according to SEQ ID NO:1, selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one amino acid substitution at at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, based on the numbering according to SEQ ID NO:1, selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, into a starting molecule having an amino acid sequence which is at least 70% and increasingly preferably at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5% or has 100% sequence identity with the amino acid sequence given in SEQ ID NO:1 over its entire length.

Ein erfindungsgemäßes Verfahren kann ferner einen oder mehrere der folgenden Verfahrensschritte umfassen: A method according to the invention may further comprise one or more of the following method steps:

(a) Einbringen einer ein- oder mehrfachen konservativen Aminosäuresubstitution, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist; (a) introducing a single or multiple conservative amino acid substitution, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F and M216L;

(b) Veränderung der Aminosäuresequenz durch Fragmentierung, Deletions-, Insertions- oder Substitutionsmutagenese derart, dass die Protease eine Aminosäuresequenz umfasst, die über eine Länge von mindestens 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261 ,262,263, 264, 265, 266, 267, 268 oder 269 zusammenhängenden Aminosäuren mit dem Ausgangsmolekül übereinstimmt, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. (b) altering the amino acid sequence by fragmentation, deletion, insertion or substitution mutagenesis such that the protease comprises an amino acid sequence which corresponds to the starting molecule over a length of at least 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268 or 269 contiguous amino acids, wherein the protease, in each case based on the numbering according to SEQ ID NO: 1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L.

Sämtliche Ausführungsformen gelten auch für die erfindungsgemäßen Verfahren. All embodiments also apply to the methods according to the invention.

In einer weiteren Ausführungsform der Erfindung ist eine zuvor beschriebene Protease stabilisiert, insbesondere durch eine oder mehrere Mutationen, z.B. Substitutionen, oder durch Kopplung an ein Polymer. Eine Erhöhung der Stabilität bei der Lagerung und/oder während des Einsatzes, z.B. beim Waschprozess, führt dazu, dass die enzymatische Aktivität länger anhält und damit die Reinigungsleistung verbessert wird. Grundsätzlich kommen alle im Stand der Technik beschriebenen und/oder zweckmäßigen Stabilisierungsmöglichkeiten in Betracht. Bevorzugt sind solche Stabilisierungen, die über Mutationen des Enzyms selbst erreicht werden, da solche Stabilisierungen im Anschluss an die Gewinnung des Enzyms keine weiteren Arbeitsschritte erfordern. Beispiele für hierfür geeignete Sequenzveränderungen sind vorstehend genannt. Weitere geeignete Sequenzveränderungen sind aus dem Stand der Technik bekannt. In a further embodiment of the invention, a previously described protease is stabilized, in particular by one or more mutations, e.g., substitutions, or by coupling to a polymer. Increasing stability during storage and/or use, e.g., during the washing process, results in longer-lasting enzymatic activity and thus improved cleaning performance. In principle, all stabilization options described and/or expedient in the prior art are contemplated. Preference is given to stabilizations achieved via mutations of the enzyme itself, since such stabilizations do not require any further steps following the isolation of the enzyme. Examples of suitable sequence modifications are mentioned above. Other suitable sequence modifications are known from the prior art.

Weitere Möglichkeiten der Stabilisierung sind z.B.: Other stabilization options include:

Veränderung der Bindung von Metallionen, insbesondere der Calcium-Bindungsstellen, z.B. durch Austauschen von einer oder mehreren der an der Calcium-Bindung beteiligten Aminosäure(n) gegen eine oder mehrere negativ geladene Aminosäuren und/oder durch Einführen von Sequenzveränderungen in mindestens einer der Folgen der beiden Aminosäuren Arginin/Glycin; Schutz gegen den Einfluss von denaturierenden Agentien wie Tensiden durch Mutationen, die eine Veränderung der Aminosäuresequenz auf oder an der Oberfläche des Proteins bewirken; Alteration of the binding of metal ions, in particular of the calcium binding sites, e.g. by exchanging one or more of the amino acid(s) involved in calcium binding for one or more negatively charged amino acids and/or by introducing sequence changes in at least one of the sequences of the two amino acids arginine/glycine; Protection against the influence of denaturing agents such as surfactants through mutations that cause a change in the amino acid sequence on or at the surface of the protein;

Austausch von Aminosäuren, die nahe dem N-Terminus liegen, gegen solche, die vermutlich über nicht-kovalente Wechselwirkungen mit dem Rest des Moleküls in Kontakt treten und somit einen Beitrag zur Aufrechterhaltung der globulären Struktur leisten. Exchange of amino acids located near the N-terminus for those that presumably come into contact with the rest of the molecule via non-covalent interactions and thus contribute to maintaining the globular structure.

Bevorzugte Ausführungsformen sind solche, bei denen das Enzym auf mehrere Arten stabilisiert wird, da mehrere stabilisierende Mutationen additiv oder synergistisch wirken. Preferred embodiments are those in which the enzyme is stabilized in several ways, since several stabilizing mutations act additively or synergistically.

Alternativ oder ergänzend kann die erfindungsgemäße Protease mit mindestens einer reversiblen Inhibitorverbindung, die aus der aus Peptidinhibitoren, insbesondere Peptidaldehyden, Polyolen, insbesondere Glycerin und 1 ,2-Propylenglykol, Benzamidinhydrochlorid, Borax, Borsäuren, Boronsäuren oder deren Salze oder Ester oder Derivate, insbesondere Phenylboronsäurederivate oder 4-Formylphenylboronsäure (4-FPBA), Verbindungen der Formeln (I) oder (II)

Figure imgf000097_0001
wobei R jeweils ausgewählt ist aus -COOH, Ci-6-Alkyl-substituierten oder unsubstituierten C2-6- Dicarbonsäuren, Ci-6-Alkyl-substituierten oder unsubstituierten C2-6-Carbonsäuren und -OOC-NR22, wobei R2 gleich oder verschieden und ausgewählt aus Ci-s-Alkyl oder H sind, sowie Salzen, Estern oder Derivaten davon, vorzugsweise Benzoesäure, Phenylmalonsäure, Benzylmalonsäure, Phenylbernsteinsäure, Benzylbernsteinsäure, Methyl-3-Benzoylpropionat, (S)-3-Phenylbuttersäure und Benzylcarbamat, und Kombinationen davon bestehenden Gruppe ausgewählt ist, kombiniert werden, um die Stabilität der Protease in Wasch- und Reinigungsmitteln weiter zu erhöhen. Alternatively or additionally, the protease according to the invention can be reacted with at least one reversible inhibitor compound selected from the group consisting of peptide inhibitors, in particular peptide aldehydes, polyols, in particular glycerol and 1,2-propylene glycol, benzamidine hydrochloride, borax, boric acids, boronic acids or their salts or esters or derivatives, in particular phenylboronic acid derivatives or 4-formylphenylboronic acid (4-FPBA), compounds of the formulas (I) or (II)
Figure imgf000097_0001
wherein R is in each case selected from -COOH, C 1-6 alkyl-substituted or unsubstituted C 2-6 dicarboxylic acids, C 1-6 alkyl-substituted or unsubstituted C 2-6 carboxylic acids and -OOC-NR 2 2, wherein R 2 is the same or different and is selected from C 1-5 alkyl or H, and salts, esters or derivatives thereof, preferably benzoic acid, phenylmalonic acid, benzylmalonic acid, phenylsuccinic acid, benzylsuccinic acid, methyl 3-benzoylpropionate, (S)-3-phenylbutyric acid and benzylcarbamate, and combinations thereof, in order to further increase the stability of the protease in detergents and cleaning agents.

In einer weiteren Ausführungsform der Erfindung ist die Protease dadurch gekennzeichnet, dass ihre Reinigungsleistung gegenüber dem Wildtypenzym (SEQ ID NO:1) (Referenzprotease) nicht signifikant verringert ist, d.h. mindestens 80% der Referenzwasch- oder -reinigungsleistung besitzt, vorzugsweise mindestens 100%, noch bevorzugter mindestens 110%, besonders bevorzugt mindestens 120% oder mehr. In a further embodiment of the invention, the protease is characterized in that its cleaning performance is not significantly reduced compared to the wild-type enzyme (SEQ ID NO:1) (reference protease), i.e. it has at least 80% of the reference washing or cleaning performance, preferably at least 100%, more preferably at least 110%, particularly preferably at least 120% or more.

Unter wasch- bzw. Reinigungsleistung wird das Vermögen eines Wasch- oder Reinigungsmittels, eine vorhandene Anschmutzung teilweise oder vollständig zu entfernen, verstanden. Im Rahmen der Erfindung weist sowohl das Wasch- oder Reinigungsmittel, welches die Protease umfasst bzw. die durch dieses Mittel gebildete Wasch- oder Reinigungsflotte, als auch die Protease selbst eine jeweilige Reinigungsleistung auf. Die Reinigungsleistung der Protease trägt somit zur Reinigungsleistung des Mittels bzw. der durch das Mittel gebildeten Wasch- oder Reinigungsflotte bei. Washing or cleaning performance refers to the ability of a washing or cleaning agent to partially or completely remove existing soiling. Within the scope of the invention, both the washing or cleaning agent comprising the protease or the washing or cleaning liquor formed by this agent, as well as the protease itself, exhibit a respective cleaning performance. The cleaning performance of the protease thus contributes to the cleaning performance of the agent or the washing or cleaning liquor formed by the agent.

Unter wasch- bzw. Reinigungsflotte wird diejenige das Wasch- oder Reinigungsmittel enthaltende Gebrauchslösung verstanden, die auf Textilien oder Gewebe bzw. harten Oberflächen, insbesondere Geschirr, einwirkt und damit mit den auf den Textilien oder Geweben bzw. harten Oberflächen, insbesondere Geschirr, vorhandenen Anschmutzungen in Kontakt kommt. Üblicherweise entsteht die Wasch- bzw. Reinigungsflotte, wenn der Wasch- bzw. Reinigungsvorgang beginnt und das Wasch- oder Reinigungsmittel z.B. in einer Wasch- oder Spülmaschine oder in einem anderen geeigneten Behältnis mit Wasser verdünnt wird. Die Reinigungsleistung kann in einem Waschsystem bestimmt werden, das ein Waschmittel in einer Dosierung zwischen 2,0 und 8,0 Gramm pro Liter Waschflotte sowie die Protease enthält. Die zu vergleichenden Proteasen werden konzentrationsgleich (bezogen auf aktives Protein) eingesetzt. Die Konzentration der Protease in dem für ein solches Waschsystem bestimmten Waschmittel beträgt 0,001 bis 0,1 Gew.-%, vorzugsweise 0,01 bis 0,06 Gew.-%, bezogen auf aktives Protein. The term "washing or cleaning liquor" refers to the working solution containing the washing or cleaning agent that acts on textiles or fabrics or hard surfaces, especially dishes, and thus comes into contact with the soiling present on the textiles or fabrics or hard surfaces, especially dishes. The washing or cleaning liquor is usually created when the washing or cleaning process begins and the washing or cleaning agent is diluted with water, e.g., in a washing machine, dishwasher, or other suitable container. The cleaning performance can be determined in a washing system containing a detergent at a dosage of between 2.0 and 8.0 grams per liter of wash liquor and the protease. The proteases to be compared are used at the same concentration (based on active protein). The protease concentration in the detergent intended for such a washing system is 0.001 to 0.1 wt.%, preferably 0.01 to 0.06 wt.%, based on active protein.

Ein flüssiges Referenzwaschmittel für ein solches Waschsystem kann z.B. wie folgt zusammengesetzt sein (alle Angaben in Gewichts-Prozent (Gew .-%)): 4,4% Alkylbenzolsulfonsäure, 5,6% weitere anionische Tenside, 2,4% C12-18 Na-Salze von Fettsäuren (Seifen), 4,4% nicht-ionische Tenside, 0,2% Phosphonate, 1 ,4% Zitronensäure, 0,95% NaOH, 0,01% Entschäumer, 2% Glycerin, 0,08% Konservierungsstoffe, 1% Ethanol, Rest demineralisiertes Wasser. Bevorzugt beträgt die Dosierung des flüssigen Waschmittels zwischen 4,5 und 6,0 Gramm pro Liter Waschflotte, z.B. 4,7, 4,9 oder 5,9 Gramm pro Liter Waschflotte. Bevorzugt wird gewaschen in einem pH-Wertebereich zwischen pH 7 und pH 10,5, bevorzugt zwischen pH 8 und pH 9. A liquid reference detergent for such a washing system can, for example, be composed as follows (all data in percent by weight (wt.%)): 4.4% alkylbenzenesulfonic acid, 5.6% other anionic surfactants, 2.4% C12-18 Na salts of fatty acids (soaps), 4.4% non-ionic surfactants, 0.2% phosphonates, 1.4% citric acid, 0.95% NaOH, 0.01% defoamers, 2% glycerol, 0.08% preservatives, 1% ethanol, and the remainder demineralized water. The preferred dosage of the liquid detergent is between 4.5 and 6.0 grams per liter of wash liquor, e.g., 4.7, 4.9, or 5.9 grams per liter of wash liquor. Washing is preferably carried out in a pH range between pH 7 and pH 10.5, preferably between pH 8 and pH 9.

Alternativ kein ein flüssiges Referenzwaschmittel für ein solches Waschsystem wie folgt zusammengesetzt sein (alle Angaben in Gewichts-Prozent): 0,3-0, 5% Xanthan, 0,2-0, 4% Anti- Schaummittel, 6-7% Glycerin, 0,3-0, 5% Ethanol, 4-7% FAEOS (Fettalkoholethersulfat), 5-15% nichtionische Tenside, 5-15% anionische Tenside (LAS), 1% Borsäure, 1-4% Natriumcitrat (Dihydrat), 2-4% Soda, 2-6% Kokosnuss-Fettsäuren, 0,5-2, 5% HEDP (1-Hydroxyethan-(1 ,1-di-phosphonsäure)), 0-0,4% PVP (Polyvinylpyrrolidon), 0-0,15% optischer Aufheller, 0-0,001% Farbstoff, Rest demineralisiertes Wasser. Bevorzugt beträgt die Dosierung des flüssigen Waschmittels zwischen 3,5 und 6,0 Gramm pro Liter Waschflotte, z.B. 4,7, 4,9 oder 5,9 Gramm pro Liter Waschflotte. Bevorzugt wird gewaschen in einem pH-Wertebereich zwischen pH 8 und pH 10,5, bevorzugt zwischen pH 8 und pH 9. Alternatively, a liquid reference detergent for such a washing system should be composed as follows (all information in percent by weight): 0.3-0.5% xanthan gum, 0.2-0.4% anti-foam agent, 6-7% glycerin, 0.3-0.5% ethanol, 4-7% FAEOS (fatty alcohol ether sulfate), 5-15% non-ionic surfactants, 5-15% anionic surfactants (LAS), 1% boric acid, 1-4% sodium citrate (dihydrate), 2-4% soda, 2-6% coconut fatty acids, 0.5-2.5% HEDP (1-hydroxyethane-(1,1-di-phosphonic acid)), 0-0.4% PVP (polyvinylpyrrolidone), 0-0.15% optical brightener, 0-0.001% dye, balance demineralized water. The dosage of the liquid detergent is preferably between 3.5 and 6.0 grams per liter of wash liquor, e.g., 4.7, 4.9, or 5.9 grams per liter of wash liquor. Washing is preferably carried out in a pH range between pH 8 and pH 10.5, preferably between pH 8 and pH 9.

Ein pulverförmiges Referenzwaschmittel für ein solches Waschsystem kann wie folgt zusammengesetzt sein (alle Angaben in Gewichts-Prozent): 10% lineares Alkylbenzolsulfonat (Natrium-Salz), 1 ,5% Ci2-18-Fettalkoholsulfat (Natrium-Salz), 2,0% C s-Fettalkohol mit 7 EO, 20% Natriumcarbonat, 6,5% Natriumhydrogencarbonat, 4,0% amorphes Natriumdisilikat, 17% Natriumcarbonatperoxohydrat, 4,0% TAED, 3,0% Polyacrylat, 1 ,0% Carboxymethylcellulose, 1 ,0% Phosphonat, 27% Natriumsulfat, Rest: Schauminhibitoren, optischer Aufheller, Duftstoffe. Bevorzugt beträgt die Dosierung des pulverförmigen Waschmittels zwischen 4,5 und 7,0 Gramm pro Liter Waschflotte, z.B. und besonders bevorzugt 4,7 Gramm pro Liter Waschflotte, oder 5,5, 5,9 oder 6,7 Gramm pro Liter Waschflotte. Bevorzugt wird gewaschen in einem pH-Wertebereich zwischen pH 9 und pH 11 . A powdered reference detergent for such a washing system can be composed as follows (all data in percent by weight): 10% linear alkylbenzenesulfonate (sodium salt), 1.5% Ci2-18 fatty alcohol sulfate (sodium salt), 2.0% C s fatty alcohol with 7 EO, 20% sodium carbonate, 6.5% sodium hydrogen carbonate, 4.0% amorphous sodium disilicate, 17% sodium carbonate peroxohydrate, 4.0% TAED, 3.0% polyacrylate, 1.0% carboxymethylcellulose, 1.0% phosphonate, 27% sodium sulfate, remainder: foam inhibitors, optical brightener, perfumes. The dosage of the powdered detergent is preferably between 4.5 and 7.0 grams per liter of wash liquor, e.g., and particularly preferably, 4.7 grams per liter of wash liquor, or 5.5, 5.9, or 6.7 grams per liter of wash liquor. Washing is preferably carried out in a pH range between pH 9 and pH 11.

Die Reinigungsleistung wird gegenüber einer Anschmutzung auf Baumwolle durch Messung des Reinigungsgrades der gewaschenen Textilien bestimmt. Beispielsweise kann der Waschvorgang für 60 Minuten bei einer Temperatur von etwa 20°C oder etwa 40°C erfolgen und das Wasser eine Wasserhärte zwischen 15,5°dH und 16,5°dH (deutsche Härte) aufweisen. Im Rahmen der Erfindung erfolgt die Bestimmung der Reinigungsleistung z.B. bei 20°C oder 40°C unter Verwendung eines flüssigen Waschmittels wie hierin angegebenen, wobei der Waschvorgang vorzugsweise für 60 Minuten bei 600 rpm erfolgt. Der Weißegrad, d.h. die Aufhellung der Anschmutzungen, als Maß für die Reinigungsleistung wird mit optischen Messverfahren bestimmt, bevorzugt photometrisch. Ein hierfür geeignetes Gerät ist z.B. das Spektrometer Minolta CM508d. Üblicherweise werden die für die Messung eingesetzten Geräte zuvor mit einem Weißstandard, bevorzugt einem mitgelieferten Weißstandard, kalibriert. The cleaning performance is determined for soiling on cotton by measuring the degree of cleaning of the washed textiles. For example, the washing process can be carried out for 60 minutes at a temperature of approximately 20°C or approximately 40°C, and the water can have a water hardness between 15.5°dH and 16.5°dH (German hardness). Within the scope of the invention, the cleaning performance is determined, for example, at 20°C or 40°C using a liquid detergent as specified herein, with the washing process preferably being carried out for 60 minutes at 600 rpm. The degree of whiteness, i.e., the lightening of soils, as a measure of cleaning performance, is determined using optical measuring methods, preferably photometrically. A suitable device for this purpose is the Minolta CM508d spectrometer. The devices used for the measurement are usually calibrated beforehand with a white standard, preferably one supplied with the product.

Die Reinigungsleistung eines Geschirrspülmittels kann in einem System bestimmt werden, das ein Maschinengeschirrspülmittel in einer Dosierung wie hierin angegeben sowie die erfindungsgemäße Protease enthält, wobei die zu vergleichenden Proteasen konzentrationsgleich (bezogen auf aktives Protein) eingesetzt sind und die Reinigungsleistung gegenüber einer Anschmutzung von Tee, Fleisch, Spaghetti und/oder Creme Brülee gemäß IKW Methode (Recommendations for the Quality Assessment of the Cleaning Performance of Dishwasher Detergents (Part B, Update 2015), sofwjournal, 142, 06/16, 34-48) in einer Miele GSL (Programm 45°C, 21 °dH) bestimmt wird. Die Konzentration der Protease in dem für dieses Waschsystem bestimmten Mittels beträgt 0,001 bis 0,1 Gew.-%, vorzugsweise 0,01 bis 0,06 Gew.-%, bezogen auf aktives, gereinigtes Protein. The cleaning performance of a dishwashing detergent can be determined in a system containing an automatic dishwashing detergent in a dosage as stated herein and the protease according to the invention, wherein the proteases to be compared are used at the same concentration (based on active protein) and the cleaning performance against a soiling of tea, meat, spaghetti and/or crème brûlée is determined according to the IKW method (Recommendations for the Quality Assessment of the Cleaning Performance of Dishwasher Detergents (Part B, Update 2015), sofwjournal, 142, 06/16, 34-48) in a Miele GSL (program 45°C, 21 °dH). The concentration of the protease in the detergent intended for this washing system is 0.001 to 0.1 wt.%, preferably 0.01 to 0.06 wt.%, based on active, purified protein.

Flüssiges Geschirrspülmittel (Zweikomponentenformulierunq):

Figure imgf000099_0001
Figure imgf000100_0001
Liquid dishwashing detergent (two-component formulation):
Figure imgf000099_0001
Figure imgf000100_0001

Festes Geschirrspülmittel:

Figure imgf000100_0002
Solid dishwashing detergent:
Figure imgf000100_0002

Durch den aktivitätsgleichen Einsatz der jeweiligen Enzyme wird sichergestellt, dass auch bei einem etwaigen Auseinanderklaffen des Verhältnisses von Aktivsubstanz zu Gesamtprotein (die Werte der spezifischen Aktivität) die jeweiligen enzymatischen Eigenschaften, also z.B. die Reinigungsleistung an bestimmten Anschmutzungen, verglichen werden. Generell gilt, dass eine niedrige spezifische Aktivität durch Zugabe einer größeren Proteinmenge ausgeglichen werden kann. Ferner können die zu untersuchenden Enzyme auch in gleicher Stoffmenge oder Gewichtsmenge eingesetzt werden, falls die zu untersuchenden Enzyme in einem Aktivitätstest eine unterschiedliche Affinität an das Testsubstrat aufweisen. Der Ausdruck "gleiche Stoffmenge" bezieht sich in diesem Zusammenhang auf eine molgleiche Verwendung der zu untersuchenden Enzyme. Der Ausdruck "gleiche Gewichtsmenge" bezieht sich auf einen gewichtsgleichen Einsatz der zu untersuchenden Enzyme. By using the respective enzymes with the same activity, it is ensured that even if there is a possible discrepancy in the ratio of active substance to total protein (the specific activity values), the respective enzymatic properties, such as the cleaning performance on specific soils, can be compared. Generally speaking, a low specific activity can be compensated by adding a larger amount of protein. Furthermore, the enzymes to be tested can also be used in the same amount of substance or weight if the enzymes to be tested show a different affinity for the test substrate in an activity test. The term "same amount of substance" in this This refers to the use of the same moles of the enzymes being tested. The term "equal weight" refers to the use of the same weight of the enzymes being tested.

Bevorzugte Ausführungsformen erfindungsgemäßer Proteasen erzielen solche vorteilhaften Reinigungsleistungen auch schon bei niedrigen Temperaturen, insbesondere in den Temperaturbereichen zwischen etwa 20°C und etwa 75°C, bevorzugt zwischen etwa 30°C und etwa 60°C und besonders bevorzugt zwischen etwa 40°C und etwa 55°C. Preferred embodiments of proteases according to the invention achieve such advantageous cleaning performance even at low temperatures, in particular in the temperature ranges between about 20°C and about 75°C, preferably between about 30°C and about 60°C and particularly preferably between about 40°C and about 55°C.

Verfahren zur Bestimmung der Protease-Aktivität dem Fachmann auf dem Gebiet der Enzymtechnologie geläufig und werden von ihm routinemäßig angewendet. Beispielsweise sind solche Verfahren offenbart in Tenside, Band 7, 1970, S. 125-132. Alternativ kann die Protease- Aktivität über die Freisetzung des Chromophors para-Nitroanilin (pNA) aus dem Substrat suc-L-Ala-L- Ala-L-Pro-L-Phe-p-Nitroanilid (AAPF) bestimmt werden. Die Protease spaltet das Substrat und setzt pNA frei. Die Freisetzung des pNA verursacht eine Zunahme der Extinktion bei 410 nm, deren zeitlicher Verlauf ein Maß für die enzymatische Aktivität ist (vgl. Del Mar et al., 1979). Die Messung erfolgt bei einer Temperatur von 25°C, bei pH 8,6, und einer Wellenlänge von 410 nm. Die Messzeit beträgt 5 min und das Messintervall 20 s bis 60 s. Die Protease-Aktivität wird üblicherweise in Protease-Einheiten (PE) angegeben. Geeignete Protease-Aktivitäten betragen z.B. 2,25, 5 oder 10 PE pro ml Waschflotte. Die Protease-Aktivität ist jedoch nicht gleich Null. Methods for determining protease activity are familiar to those skilled in the field of enzyme technology and are routinely used by them. For example, such methods are disclosed in Tenside, Volume 7, 1970, pp. 125-132. Alternatively, protease activity can be determined via the release of the chromophore para-nitroaniline (pNA) from the substrate suc-L-Ala-L-Ala-L-Pro-L-Phe-p-nitroanilide (AAPF). The protease cleaves the substrate and releases pNA. The release of pNA causes an increase in absorbance at 410 nm, the time course of which is a measure of enzymatic activity (cf. Del Mar et al., 1979). The measurement is performed at a temperature of 25°C, pH 8.6, and a wavelength of 410 nm. The measurement time is 5 minutes, and the measurement interval is 20 to 60 seconds. Protease activity is usually expressed in protease units (PU). Suitable protease activities are, for example, 2.25, 5, or 10 PU per ml of wash liquor. However, protease activity is not zero.

Ein alternativer Test zur Feststellung der proteolytischen Aktivität der erfindungsgemäßen Proteasen ist ein optisches Messverfahren, bevorzugt ein photometrisches Verfahren. Der hierfür geeignete Test umfasst die Protease-abhängige Spaltung des Substratproteins Casein. Dieses wird durch die Protease in eine Vielzahl kleinerer Teilprodukte gespalten. Die Gesamtheit dieser Teilprodukte weist eine erhöhte Absorption bei 290 nm gegenüber nicht gespaltenem Casein auf, wobei diese erhöhte Absorption unter Verwendung eines Photometers ermittelt werden und somit ein Rückschluss auf die enzymatische Aktivität der Protease gezogen werden kann. An alternative test for determining the proteolytic activity of the proteases according to the invention is an optical measurement method, preferably a photometric method. The test suitable for this purpose involves the protease-dependent cleavage of the substrate protein casein. This is cleaved by the protease into a multitude of smaller partial products. The totality of these partial products exhibits an increased absorption at 290 nm compared to non-cleaved casein. This increased absorption can be determined using a photometer, thus allowing conclusions to be drawn about the enzymatic activity of the protease.

Die Proteinkonzentration kann mit Hilfe bekannter Methoden, zum Beispiel dem BCA-Verfahren (Bicinchoninsäure; 2,2‘-Bichinolyl-4,4‘-dicarbonsäure) oder dem Biuret-Verfahren (Gornall et al., J. Biol. Chem. 177, 1948, 751-766) bestimmt werden. Die Bestimmung der Aktivproteinkonzentration kann diesbezüglich über eine Titration der aktiven Zentren unter Verwendung eines geeigneten irreversiblen Inhibitors und Bestimmung der Restaktivität (vgl. Bender et al., J. Am. Chem. Soc. 1966, 88, 24, 5890-5913) erfolgen. The protein concentration can be determined using known methods, for example, the BCA method (bicinchoninic acid; 2,2'-biquinolyl-4,4'-dicarboxylic acid) or the biuret method (Gornall et al., J. Biol. Chem. 177, 1948, 751-766). The determination of the active protein concentration can be achieved by titrating the active sites using a suitable irreversible inhibitor and determining the residual activity (cf. Bender et al., J. Am. Chem. Soc. 1966, 88, 24, 5890-5913).

Ein weiterer Gegenstand der Erfindung ist eine Protease wie hierin beschrieben, die dadurch gekennzeichnet ist, dass sie mindestens eine chemische Modifikation aufweist. Eine Protease mit einer solchen Veränderung wird als Derivat bezeichnet, d.h. die Protease ist derivatisiert. Unter Derivaten werden im Sinne der vorliegenden Anmeldung demnach solche Proteine verstanden, deren reine Aminosäurekette chemisch modifiziert worden ist. Solche Derivatisierungen können z.B. in vivo durch die Wirtszelle erfolgen, die das Protein exprimiert. Diesbezüglich sind Kopplungen niedrigmolekularer Verbindungen wie von Lipiden oder Oligosacchariden besonders hervorzuheben. Derivatisierungen können aber auch in vitro durchgeführt werden, etwa durch die chemische Umwandlung einer Seitenkette einer Aminosäure oder durch kovalente Bindung einer anderen Verbindung an das Protein. Beispielsweise ist die Kopplung von Aminen an Carboxylgruppen eines Enzyms zur Veränderung des isoelektrischen Punkts möglich. Eine solche andere Verbindung kann auch ein weiteres Protein sein, das z.B. über bifunktionelle chemische Verbindungen an ein erfindungsgemäßes Protein gebunden wird. Ebenso ist unter Derivatisierung die kovalente Bindung an einen makromolekularen Träger zu verstehen, oder auch ein nichtkovalenter Einschluss in geeignete makromolekulare Käfigstrukturen. Derivatisierungen können z.B. die Substratspezifität oder die Bindungsstärke an das Substrat beeinflussen oder eine vorübergehende Blockierung der enzymatischen Aktivität herbeiführen, wenn es sich bei der angekoppelten Substanz um einen Inhibitor handelt. Dies kann z.B. für den Zeitraum der Lagerung sinnvoll sein. Derartige Modifikationen können ferner die Stabilität oder die enzymatische Aktivität beeinflussen. Sie können ferner auch dazu dienen, die Allergenizität und/oder Immunogenizität des Proteins herabzusetzen und damit z.B. dessen Hautverträglichkeit zu erhöhen. Beispielsweise können Kopplungen mit makromolekularen Verbindungen, z.B. Polyethylenglykol, das Protein hinsichtlich der Stabilität und/oder Hautverträglichkeit verbessern. Unter Derivaten eines erfindungsgemäßen Proteins können im weitesten Sinne auch Präparationen dieser Proteine verstanden werden. Je nach Gewinnung, Aufarbeitung oder Präparation kann ein Protein mit diversen anderen Stoffen kombiniert sein, z.B. aus der Kultur der produzierenden Mikroorganismen. Ein Protein kann auch, z.B. zur Erhöhung seiner Lagerstabilität, mit anderen Stoffen gezielt versetzt worden sein. Erfindungsgemäß sind deshalb auch alle Präparationen eines erfindungsgemäßen Proteins. Das ist auch unabhängig davon, ob es in einer bestimmten Präparation tatsächlich diese enzymatische Aktivität entfaltet oder nicht. Denn es kann gewünscht sein, dass es bei der Lagerung keine oder nur geringe Aktivität besitzt, und erst zum Zeitpunkt der Verwendung seine enzymatische Funktion entfaltet. Dies kann z.B. über entsprechende Begleitstoffe gesteuert werden. Insbesondere die gemeinsame Präparation von Proteasen mit spezifischen Inhibitoren ist diesbezüglich möglich. Unter allen hierin beschriebenen Proteasen beziehungsweise Protease-Varianten und/oder -Derivaten sind im Rahmen der vorliegenden Erfindung diejenigen besonders bevorzugt, deren Lagerstabilität und/oder katalytische Aktivität und/oder Substrattoleranz und/oder Reinigungsleistung gegenüber einer Referenzprotease verbessert ist, wobei die katalytische Aktivität und/oder Reinigungsleistung wie hierin beschrieben bestimmt wird. The invention further relates to a protease as described herein, which is characterized in that it has at least one chemical modification. A protease with such a modification is referred to as a derivative, i.e. the protease is derivatized. Derivatives in the sense of the present application are understood to be proteins whose pure amino acid chain has been chemically modified. Such derivatizations can, for example, take place in vivo by the host cell expressing the protein. Coupling of low-molecular compounds such as lipids or oligosaccharides is particularly noteworthy in this regard. Derivatizations can, however, also be carried out in vitro, for example by chemically converting a side chain of an amino acid or by covalently binding another Connection to the protein. For example, the coupling of amines to carboxyl groups of an enzyme is possible to change the isoelectric point. Such another connection can also be another protein that is bound to a protein according to the invention, for example, via bifunctional chemical compounds. Derivatization is also understood to mean covalent binding to a macromolecular carrier, or noncovalent inclusion in suitable macromolecular cage structures. Derivatizations can, for example, influence the substrate specificity or the binding strength to the substrate, or temporarily block enzymatic activity if the coupled substance is an inhibitor. This can be useful, for example, for the storage period. Such modifications can also influence stability or enzymatic activity. They can also serve to reduce the allergenicity and/or immunogenicity of the protein and thus, for example, increase its skin compatibility. For example, coupling with macromolecular compounds, e.g., polyethylene glycol, can improve the protein in terms of stability and/or skin compatibility. Derivatives of a protein according to the invention can, in the broadest sense, also be understood to include preparations of these proteins. Depending on the method of extraction, processing, or preparation, a protein can be combined with various other substances, e.g., from the culture of the producing microorganisms. A protein can also be deliberately mixed with other substances, e.g., to increase its storage stability. Therefore, all preparations of a protein according to the invention are also according to the invention. This is independent of whether or not it actually exhibits this enzymatic activity in a particular preparation. It can be desired that it has no or only low activity during storage and only exhibits its enzymatic function at the time of use. This can be controlled, for example, via appropriate accompanying substances. In particular, the joint preparation of proteases with specific inhibitors is possible in this regard. Of all the proteases or protease variants and/or derivatives described herein, those whose storage stability and/or catalytic activity and/or substrate tolerance and/or purification performance is improved compared to a reference protease are particularly preferred within the scope of the present invention, wherein the catalytic activity and/or purification performance is determined as described herein.

Ein weiterer Gegenstand der Erfindung ist eine Nukleinsäure, die für eine erfindungsgemäße Protease codiert, sowie ein Vektor enthaltend eine solche Nukleinsäure, insbesondere ein Klonierungsvektor oder ein Expressionsvektor. Hierbei kann es sich um DNA- oder RNA-Moleküle handeln. Sie können als Einzelstrang, als ein zu diesem Einzelstrang komplementärer Einzelstrang oder als Doppelstrang vorliegen. Insbesondere bei DNA-Molekülen sind die Sequenzen beider komplementärer Stränge in jeweils allen drei möglichen Leserastern zu berücksichtigen. Ferner ist zu berücksichtigen, dass verschiedene Codons, also Basentriplets, für die gleichen Aminosäuren codieren können, so dass eine bestimmte Aminosäuresequenz von mehreren unterschiedlichen Nukleinsäuren codiert werden kann. Auf Grund dieser Degeneriertheit des genetischen Codes sind sämtliche Nukleinsäuresequenzen in diesem Erfindungsgegenstand eingeschlossen, die eine der vorstehend beschriebenen Proteasen codieren können. Der Fachmann ist in der Lage, diese Nukleinsäuresequenzen zweifelsfrei zu bestimmen, da trotz der Degeneriertheit des genetischen Codes einzelnen Codons definierte Aminosäuren zuzuordnen sind. Daher kann der Fachmann ausgehend von einer Aminosäuresequenz für diese Aminosäuresequenz codierende Nukleinsäuren problemlos ermitteln. Weiterhin können bei erfindungsgemäßen Nukleinsäuren ein oder mehrere Codons durch synonyme Codons ersetzt sein. Dieser Aspekt bezieht sich insbesondere auf die heterologe Expression der erfindungsgemäßen Enzyme. So besitzt jeder Organismus, z.B. eine Wirtszelle eines Produktionsstammes, eine bestimmte Codon-Verwendung. Unter Codon-Verwendung wird die Übersetzung des genetischen Codes in Aminosäuren durch den jeweiligen Organismus verstanden. Es kann zu Engpässen in der Proteinbiosynthese kommen, wenn die auf der Nukleinsäure liegenden Codons in dem Organismus einer vergleichsweise geringen Zahl von beladenen tRNA-Molekülen gegenüberstehen. Obwohl für die gleiche Aminosäure codierend führt das dazu, dass in dem Organismus ein Codon weniger effizient translatiert wird als ein synonymes Codon, das für dieselbe Aminosäure codiert. Auf Grund des Vorliegens einer höheren Anzahl von tRNA- Molekülen für das synonyme Codon kann dieses in dem Organismus effizienter translatiert werden. The invention further relates to a nucleic acid encoding a protease according to the invention, as well as to a vector containing such a nucleic acid, in particular a cloning vector or an expression vector. These can be DNA or RNA molecules. They can be present as a single strand, as a single strand complementary to this single strand, or as a double strand. Particularly in the case of DNA molecules, the sequences of both complementary strands must be taken into account in all three possible reading frames. Furthermore, it must be taken into account that different codons, i.e., base triplets, can code for the same amino acids, so that a specific amino acid sequence can be encoded by several different nucleic acids. Due to this degeneracy of the genetic code, all nucleic acid sequences that can encode one of the proteases described above are included in this subject matter of the invention. The skilled person is able to determine these nucleic acid sequences without any doubt, since, despite the degeneracy of the genetic code, defined amino acids can be assigned to individual codons. Therefore, the skilled person can Starting from an amino acid sequence, nucleic acids coding for this amino acid sequence can be easily determined. Furthermore, in nucleic acids according to the invention, one or more codons can be replaced by synonymous codons. This aspect relates in particular to the heterologous expression of the enzymes according to the invention. Thus, every organism, e.g. a host cell of a production strain, has a specific codon usage. Codon usage is understood to mean the translation of the genetic code into amino acids by the respective organism. Bottlenecks in protein biosynthesis can arise if the codons on the nucleic acid in the organism are faced with a comparatively small number of loaded tRNA molecules. Although it encodes the same amino acid, this leads to a codon being translated less efficiently in the organism than a synonymous codon that encodes the same amino acid. Due to the presence of a higher number of tRNA molecules for the synonymous codon, it can be translated more efficiently in the organism.

Einem Fachmann ist es über heutzutage allgemein bekannte Methoden, wie z.B. die chemische Synthese oder die Polymerase-Kettenreaktion (PCR) in Verbindung mit molekularbiologischen und/oder proteinchemischen Standardmethoden möglich, anhand bekannter DNA- und/oder Aminosäuresequenzen die entsprechenden Nukleinsäuren bis hin zu vollständigen Genen herzustellen. Derartige Methoden sind z.B. aus Sambrook, J., Fritsch, E.F. and Maniatis, T. 2001. Molecular cloning: a laboratory manual, 3. Edition Cold Spring Laboratory Press bekannt. Using methods commonly known today, such as chemical synthesis or the polymerase chain reaction (PCR) in conjunction with standard molecular biological and/or protein chemical methods, a person skilled in the art can produce the corresponding nucleic acids, including complete genes, based on known DNA and/or amino acid sequences. Such methods are known, for example, from Sambrook, J., Fritsch, E.F. and Maniatis, T. 2001. Molecular cloning: a laboratory manual, 3rd Edition, Cold Spring Laboratory Press.

Unter Vektoren werden im Sinne der vorliegenden Erfindung aus Nukleinsäuren bestehende Elemente verstanden, die als kennzeichnenden Nukleinsäurebereich eine erfindungsgemäße Nukleinsäure enthalten. Sie vermögen diese in einer Spezies oder einer Zelllinie über mehrere Generationen oder Zellteilungen hinweg als stabiles genetisches Element zu etablieren. Vektoren sind insbesondere bei der Verwendung in Bakterien spezielle Plasmide, also zirkulare genetische Elemente. Im Rahmen der vorliegenden Erfindung wird eine erfindungsgemäße Nukleinsäure in einen Vektor kloniert. Zu den Vektoren zählen z.B. solche, deren Ursprung bakterielle Plasmide, Viren oder Bakteriophagen sind, oder überwiegend synthetische Vektoren oder Plasmide mit Elementen verschiedenster Herkunft. Mit den weiteren jeweils vorhandenen genetischen Elementen vermögen Vektoren sich in den betreffenden Wirtszellen über mehrere Generationen hinweg als stabile Einheiten zu etablieren. Sie können extrachromosomal als eigene Einheiten vorliegen oder in ein Chromosom oder chromosomale DNA integrieren. Expressionsvektoren umfassen Nukleinsäuresequenzen, die sie dazu befähigen, in den sie enthaltenden Wirtszellen, vorzugsweise Mikroorganismen, besonders bevorzugt Bakterien, zu replizieren und dort eine enthaltene Nukleinsäure zur Expression zu bringen. Die Expression wird insbesondere von dem oder den Promotoren beeinflusst, welche die Transkription regulieren. Prinzipiell kann die Expression durch den natürlichen, ursprünglich vor der zu exprimierenden Nukleinsäure lokalisierten Promotor erfolgen, aber auch durch einen auf dem Expressionsvektor bereitgestellten Promotor der Wirtszelle oder auch durch einen modifizierten oder einen völlig anderen Promotor eines anderen Organismus oder einer anderen Wirtszelle. Im vorliegenden Fall wird zumindest ein Promotor für die Expression einer erfindungsgemäßen Nukleinsäure zur Verfügung gestellt und für deren Expression genutzt. Expressionsvektoren können ferner regulierbar sein, z.B. durch Änderung der Kultivierungsbedingungen oder bei Erreichen einer bestimmten Zelldichte der sie enthaltenen Wirtszellen oder durch Zugabe von bestimmten Substanzen, insbesondere Aktivatoren der Genexpression. Ein Beispiel für eine solche Substanz ist das Galactose-Derivat Isopropyl-ß-D- thiogalactopyranosid (IPTG), welches als Aktivator des bakteriellen Lactose-Operons (lac-Operons) verwendet wird. Im Gegensatz zu Expressionsvektoren wird die enthaltene Nukleinsäure in Klonierungsvektoren nicht exprimiert. For the purposes of the present invention, vectors are understood to be elements consisting of nucleic acids which contain a nucleic acid according to the invention as a characteristic nucleic acid region. They are capable of establishing this nucleic acid as a stable genetic element in a species or cell line over several generations or cell divisions. Vectors are special plasmids, i.e. circular genetic elements, particularly when used in bacteria. Within the scope of the present invention, a nucleic acid according to the invention is cloned into a vector. Vectors include, for example, those whose origin is bacterial plasmids, viruses or bacteriophages, or predominantly synthetic vectors or plasmids with elements of various origins. With the additional genetic elements present in each case, vectors are capable of establishing themselves as stable units in the respective host cells over several generations. They can exist extrachromosomally as independent units or integrate into a chromosome or chromosomal DNA. Expression vectors comprise nucleic acid sequences that enable them to replicate in the host cells containing them, preferably microorganisms, particularly preferably bacteria, and to express a contained nucleic acid therein. Expression is influenced in particular by the promoter(s) that regulate transcription. In principle, expression can occur through the natural promoter originally located upstream of the nucleic acid to be expressed, but also through a promoter of the host cell provided on the expression vector, or through a modified or completely different promoter of another organism or another host cell. In the present case, at least one promoter for the expression of a nucleic acid according to the invention is provided and used for its expression. Expression vectors can also be regulated, e.g., by changing the cultivation conditions or upon reaching a certain cell density of the nucleic acid containing them. Host cells or by adding certain substances, particularly gene expression activators. An example of such a substance is the galactose derivative isopropyl-ß-D-thiogalactopyranoside (IPTG), which is used as an activator of the bacterial lactose operon (lac operon). In contrast to expression vectors, the nucleic acid contained in cloning vectors is not expressed.

Ein weiterer Gegenstand der Erfindung ist eine nicht-menschliche Wirtszelle, die eine erfindungsgemäße Nukleinsäure oder einen erfindungsgemäßen Vektor beinhaltet, oder die eine erfindungsgemäße Protease beinhaltet, insbesondere eine, die die Protease in das die Wirtszelle umgebende Medium sezerniert. Bevorzugt wird eine erfindungsgemäße Nukleinsäure oder ein erfindungsgemäßer Vektor in einen Mikroorganismus transformiert, der dann eine erfindungsgemäße Wirtszelle darstellt. Alternativ können auch einzelne Komponenten, d.h. Nukleinsäure-Teile oder -Fragmente einer erfindungsgemäßen Nukleinsäure derart in eine Wirtszelle eingebracht werden, dass die dann resultierende Wirtszelle eine erfindungsgemäße Nukleinsäure oder einen erfindungsgemäßen Vektor enthält. Dieses Vorgehen eignet sich besonders dann, wenn die Wirtszelle bereits einen oder mehrere Bestandteile einer erfindungsgemäßen Nukleinsäure oder eines erfindungsgemäßen Vektors enthält und die weiteren Bestandteile dann entsprechend ergänzt werden. Verfahren zur Transformation von Zellen sind im Stand der Technik etabliert und dem Fachmann hinlänglich bekannt. Als Wirtszellen eignen sich prinzipiell alle Zellen, das heißt prokaryotische oder eukaryotische Zellen. Bevorzugt sind solche Wirtszellen, die sich genetisch vorteilhaft handhaben lassen, was z.B. die Transformation mit der Nukleinsäure oder dem Vektor und dessen stabile Etablierung angeht, z.B. einzellige Pilze oder Bakterien. Ferner zeichnen sich bevorzugte Wirtszellen durch eine gute mikrobiologische und biotechnologische Handhabbarkeit aus. Das betrifft z.B. leichte Kultivierbarkeit, hohe Wachstumsraten, geringe Anforderungen an Fermentationsmedien und gute Produktions- und Sekretionsraten für Fremdproteine. Bevorzugte erfindungsgemäße Wirtszellen sezernieren das (transgen) exprimierte Protein in das die Wirtszellen umgebende Medium. Ferner können die Proteasen von den sie produzierenden Zellen nach deren Herstellung modifiziert werden, z.B. durch Anknüpfung von Zuckermolekülen, Formylierungen, Aminierungen, usw. Solche posttranslationalen Modifikationen können die Protease funktionell beeinflussen. The invention further relates to a non-human host cell which comprises a nucleic acid according to the invention or a vector according to the invention, or which comprises a protease according to the invention, in particular one which secretes the protease into the medium surrounding the host cell. Preferably, a nucleic acid according to the invention or a vector according to the invention is transformed into a microorganism, which then represents a host cell according to the invention. Alternatively, individual components, i.e. nucleic acid parts or fragments of a nucleic acid according to the invention, can be introduced into a host cell in such a way that the resulting host cell contains a nucleic acid according to the invention or a vector according to the invention. This procedure is particularly suitable when the host cell already contains one or more components of a nucleic acid according to the invention or a vector according to the invention, and the further components are then supplemented accordingly. Methods for transforming cells are established in the prior art and sufficiently known to the person skilled in the art. In principle, all cells, i.e., prokaryotic or eukaryotic cells, are suitable as host cells. Preferred host cells are those that are genetically advantageous to handle, for example, with regard to transformation with the nucleic acid or vector and its stable establishment, e.g., unicellular fungi or bacteria. Furthermore, preferred host cells are characterized by good microbiological and biotechnological handling. This applies, for example, to easy culturability, high growth rates, low requirements for fermentation media, and good production and secretion rates for foreign proteins. Preferred host cells according to the invention secrete the (transgenically) expressed protein into the medium surrounding the host cells. Furthermore, the proteases can be modified by the cells producing them after their production, e.g., by attaching sugar molecules, formylations, aminations, etc. Such post-translational modifications can influence the function of the protease.

Weitere bevorzugte Ausführungsformen stellen solche Wirtszellen dar, die aufgrund genetischer Regulationselemente, die z.B. auf dem Vektor zur Verfügung gestellt werden, aber auch von vornherein in diesen Zellen vorhanden sein können, in ihrer Aktivität regulierbar sind. Beispielsweise durch kontrollierte Zugabe von chemischen Verbindungen, die als Aktivatoren dienen, durch Änderung der Kultivierungsbedingungen oder bei Erreichen einer bestimmten Zelldichte können diese zur Expression angeregt werden. Dies ermöglicht eine wirtschaftliche Produktion der erfindungsgemäßen Proteine. Ein Beispiel für eine solche Verbindung ist IPTG wie vorstehend beschrieben. Further preferred embodiments are host cells whose activity can be regulated by genetic regulatory elements, which are provided, for example, on the vector, but can also be present in these cells from the outset. These cells can be stimulated to express, for example, by controlled addition of chemical compounds that serve as activators, by changing the cultivation conditions, or upon reaching a certain cell density. This enables economical production of the proteins of the invention. An example of such a compound is IPTG as described above.

Bevorzugte Wirtszellen sind prokaryotische oder bakterielle Zellen. Bakterien zeichnen sich durch kurze Generationszeiten und geringe Ansprüche an die Kultivierungsbedingungen aus. Dadurch können kostengünstige Kultivierungsverfahren oder Herstellungsverfahren etabliert werden. Zudem verfügt der Fachmann bei Bakterien in der Fermentationstechnik über einen reichhaltigen Erfahrungsschatz. Für eine spezielle Produktion können aus verschiedensten, im Einzelfall experimentell zu ermittelnden Gründen wie Nährstoffquellen, Produktbildungsrate, Zeitbedarf usw., gramnegative oder grampositive Bakterien geeignet sein. Bei gramnegativen Bakterien wie z.B. Escherichia co// wird eine Vielzahl von Proteinen in den periplasmatischen Raum sezerniert, also in das Kompartiment zwischen den beiden die Zellen einschließenden Membranen. Dies kann für spezielle Anwendungen vorteilhaft sein. Ferner können auch gramnegative Bakterien so ausgestaltet werden, dass sie die exprimierten Proteine nicht nur in den periplasmatischen Raum, sondern in das das Bakterium umgebende Medium ausschleusen. Grampositive Bakterien wie z.B. Bacilli oder Actinomyceten oder andere Vertreter der Actinomyce tales besitzen demgegenüber keine äußere Membran, so dass sezernierte Proteine sogleich in das die Bakterien umgebende Medium, in der Regel das Nährmedium, abgegeben werden, aus welchem sich die exprimierten Proteine aufreinigen lassen. Sie können aus dem Medium direkt isoliert oder weiter prozessiert werden. Zudem sind grampositive Bakterien mit den meisten Herkunftsorganismen für technisch wichtige Enzyme verwandt oder identisch und bilden meist selbst vergleichbare Enzyme, so dass sie über eine ähnliche Codon-Verwendung verfügen und ihr Protein-Syntheseapparat naturgemäß entsprechend ausgerichtet ist. Erfindungsgemäße Wirtszellen können hinsichtlich ihrer Anforderungen an die Kulturbedingungen verändert sein, andere oder zusätzliche Selektionsmarker aufweisen oder noch andere oder zusätzliche Proteine exprimieren. Es kann sich insbesondere auch um solche Wirtszellen handeln, die mehrere Proteine oder Enzyme transgen exprimieren. Die vorliegende Erfindung ist prinzipiell auf alle Mikroorganismen, insbesondere auf alle fermentierbaren Mikroorganismen, besonders bevorzugt auf solche der Gattung Bacillus, anwendbar und führt dazu, dass sich durch den Einsatz solcher Mikroorganismen erfindungsgemäße Proteine herstellen lassen. Solche Mikroorganismen stellen dann Wirtszellen im Sinne der Erfindung dar. In einerweiteren Ausführungsform der Erfindung ist die Wirtszelle dadurch gekennzeichnet, dass sie ein Bakterium ist, bevorzugt eines, das ausgewählt ist aus der Gruppe der Gattungen von Escherichia, Klebsiella, Bacillus, Staphylococcus, Corynebacterium, Arthrobacter, Streptomyces, Stenotrophomonas und Pseudomonas, weiter bevorzugt eines, das ausgewählt ist aus der Gruppe von Escherichia coli, Klebsiella planticola, Bacillus licheniformis, Bacillus lentus, Bacillus amyloliquefaciens, Bacillus subtilis, Bacillus alcalophilus, Bacillus globigii, Bacillus gibsonii, Bacillus clausii, Bacillus halodurans, Bacillus pumilus, Staphylococcus carnosus, Corynebacterium glutamicum, Arthrobacter oxidans, Streptomyces lividans, Streptomyces coelicolor und Stenotrophomonas maltophilia. Preferred host cells are prokaryotic or bacterial cells. Bacteria are characterized by short generation times and low demands on cultivation conditions. This allows for the establishment of cost-effective cultivation methods or production processes. Furthermore, the specialist in bacteria in fermentation technology has a rich A wealth of experience. For a specific production process, either gram-negative or gram-positive bacteria may be suitable for a variety of reasons, which must be determined experimentally in each individual case, such as nutrient sources, product formation rate, time required, etc. In gram-negative bacteria such as Escherichia coli, a large number of proteins are secreted into the periplasmic space, i.e. into the compartment between the two membranes surrounding the cells. This can be advantageous for special applications. Furthermore, gram-negative bacteria can also be engineered so that they secrete the expressed proteins not only into the periplasmic space, but also into the medium surrounding the bacterium. Gram-positive bacteria such as Bacilli or Actinomycetes or other members of the Actinomycetes family, on the other hand, do not have an outer membrane, so that secreted proteins are immediately released into the medium surrounding the bacteria, usually the nutrient medium, from which the expressed proteins can be purified. They can be isolated directly from the medium or further processed. In addition, Gram-positive bacteria are related to or identical to most of the source organisms for technically important enzymes and usually produce comparable enzymes themselves, so that they have a similar codon usage and their protein synthesis apparatus is naturally oriented accordingly. Host cells according to the invention can be modified with regard to their requirements for culture conditions, have different or additional selection markers, or express different or additional proteins. In particular, they can also be host cells that transgenically express several proteins or enzymes. The present invention is in principle applicable to all microorganisms, in particular to all fermentable microorganisms, particularly preferably to those of the genus Bacillus, and leads to the production of proteins according to the invention through the use of such microorganisms. Such microorganisms then represent host cells within the meaning of the invention. In a further embodiment of the invention, the host cell is characterized in that it is a bacterium, preferably one selected from the group of the genera Escherichia, Klebsiella, Bacillus, Staphylococcus, Corynebacterium, Arthrobacter, Streptomyces, Stenotrophomonas and Pseudomonas, more preferably one selected from the group of Escherichia coli, Klebsiella planticola, Bacillus licheniformis, Bacillus lentus, Bacillus amyloliquefaciens, Bacillus subtilis, Bacillus alcalophilus, Bacillus globigii, Bacillus gibsonii, Bacillus clausii, Bacillus halodurans, Bacillus pumilus, Staphylococcus carnosus, Corynebacterium glutamicum, Arthrobacter oxidans, Streptomyces lividans, Streptomyces coelicolor and Stenotrophomonas maltophilia.

Die Wirtszelle kann aber auch eine eukaryotische Zelle sein, die dadurch gekennzeichnet ist, dass sie einen Zellkern besitzt. Einen weiteren Gegenstand der Erfindung stellt daher eine Wirtszelle dar, die dadurch gekennzeichnet ist, dass sie einen Zellkern besitzt. Im Gegensatz zu prokaryotischen Zellen sind eukaryotische Zellen in der Lage, das gebildete Protein posttranslational zu modifizieren. Beispiele dafür sind Pilze wie Actinomyceten oder Hefen wie Saccharomyces oder Kluyveromyces. Dies kann z.B. dann besonders vorteilhaft sein, wenn die Proteine im Zusammenhang mit ihrer Synthese spezifische Modifikationen erfahren sollen, die derartige Systeme ermöglichen. Zu den Modifikationen, die eukaryotische Systeme besonders im Zusammenhang mit der Proteinsynthese durchführen, gehören z.B. die Bindung niedermolekularer Verbindungen wie Membrananker oder Oligosaccharide. Derartige Oligosaccharid-Modifikationen können z.B. zur Senkung der Allergenizität eines exprimierten Proteins wünschenswert sein. Auch eine Co-Expression mit den natürlicherweise von derartigen Zellen gebildeten Enzymen, wie z.B. Cellulasen, kann vorteilhaft sein. Ferner können sich z.B. thermophile pilzliche Expressionssysteme besonders zur Expression temperaturbeständiger Proteine oder Varianten eignen. However, the host cell can also be a eukaryotic cell, which is characterized by having a cell nucleus. A further subject of the invention is therefore a host cell characterized by having a cell nucleus. In contrast to prokaryotic cells, eukaryotic cells are capable of post-translationally modifying the protein they produce. Examples of this are fungi such as actinomycetes or yeasts such as Saccharomyces or Kluyveromyces. This can be particularly advantageous, for example, if the proteins are to undergo specific modifications in connection with their synthesis, which enable such systems. The modifications that eukaryotic systems carry out, particularly in connection with protein synthesis, include the binding of low-molecular-weight compounds such as membrane anchors or oligosaccharides. Such oligosaccharide modifications can, for example, be used to reduce allergenicity. of an expressed protein may be desirable. Co-expression with enzymes naturally produced by such cells, such as cellulases, may also be advantageous. Furthermore, thermophilic fungal expression systems, for example, may be particularly suitable for the expression of temperature-stable proteins or variants.

Die erfindungsgemäßen Wirtszellen werden in üblicher weise kultiviert und fermentiert, z.B. in diskontinuierlichen oder kontinuierlichen Systemen. Im ersten Fall wird ein geeignetes Nährmedium mit den Wirtszellen beimpft und das Produkt nach einem experimentell zu ermittelnden Zeitraum aus dem Medium geerntet. Kontinuierliche Fermentationen zeichnen sich durch Erreichen eines Fließgleichgewichts aus, in dem über einen vergleichsweise langen Zeitraum Zellen teilweise absterben aber auch nachwachsen und gleichzeitig aus dem Medium das gebildete Protein entnommen werden kann. The host cells according to the invention are cultivated and fermented in a conventional manner, e.g., in discontinuous or continuous systems. In the former case, a suitable nutrient medium is inoculated with the host cells, and the product is harvested from the medium after a period of time to be determined experimentally. Continuous fermentations are characterized by the achievement of a steady state in which cells partially die but also regrow over a comparatively long period of time, and the formed protein can be simultaneously extracted from the medium.

Erfindungsgemäße Wirtszellen werden bevorzugt verwendet, um erfindungsgemäße Proteasen herzustellen. Ein weiterer Gegenstand der Erfindung ist daher ein Verfahren zur Herstellung einer Protease umfassend a) Kultivieren einer erfindungsgemäßen Wirtszelle, und b) Isolieren der Protease aus dem Kulturmedium oder aus der Wirtszelle. Host cells according to the invention are preferably used to produce proteases according to the invention. The invention therefore further provides a process for producing a protease comprising a) culturing a host cell according to the invention, and b) isolating the protease from the culture medium or from the host cell.

Dieser Erfindungsgegenstand umfasst bevorzugt Fermentationsverfahren. This subject matter of the invention preferably comprises fermentation processes.

Fermentationsverfahren sind an sich aus dem Stand der Technik bekannt und stellen den eigentlichen großtechnischen Produktionsschritt dar, in der Regel gefolgt von einer geeigneten Aufreinigungsmethode des hergestellten Produktes, z.B. der erfindungsgemäßen Proteasen. Alle Fermentationsverfahren, die auf einem entsprechenden Verfahren zur Herstellung einer erfindungsgemäßen Protease beruhen, stellen Ausführungsformen dieses Erfindungsgegenstandes dar. Fermentationsverfahren, die dadurch gekennzeichnet sind, dass die Fermentation über eine Zulaufstrategie durchgeführt wird, kommen insbesondere in Betracht. Hierbei werden die Medienbestandteile, die durch die fortlaufende Kultivierung verbraucht werden, zugefüttert. Hierdurch können beträchtliche Steigerungen sowohl in der Zelldichte als auch in der Zellmasse beziehungsweise Trockenmasse und/oder insbesondere in der Aktivität der interessierenden Protease erreicht werden. Ferner kann die Fermentation auch so gestaltet werden, dass unerwünschte Stoffwechselprodukte herausgefiltert oder durch Zugabe von Puffer oder jeweils passende Gegenionen neutralisiert werden. Die hergestellte Protease kann aus dem Fermentationsmedium geerntet werden. Ein solches Fermentationsverfahren ist gegenüber einer Isolation der Protease aus der Wirtszelle, d.h. einer Produktaufbereitung aus der Zellmasse (Trockenmasse) bevorzugt, erfordert jedoch die Zurverfügungstellung von geeigneten Wirtszellen oder von einem oder mehreren geeigneten Sekretionsmarkern oder -mechanismen und/oder Transportsystemen, damit die Wirtszellen die Protease in das Fermentationsmedium sezernieren. Ohne Sekretion kann alternativ die Isolation der Protease aus der Wirtszelle, d.h. eine Aufreinigung derselben aus der Zellmasse, erfolgen, z.B. durch Fällung mit Ammoniumsulfat oder Ethanol, oder durch chromatographische Reinigung. Fermentation processes are known per se from the prior art and represent the actual large-scale production step, usually followed by a suitable purification method for the manufactured product, e.g., the proteases according to the invention. All fermentation processes based on a corresponding process for producing a protease according to the invention represent embodiments of this subject matter of the invention. Fermentation processes characterized in that the fermentation is carried out via a feed strategy are particularly suitable. Here, the media components consumed by the ongoing cultivation are fed in. This allows significant increases in both cell density and cell mass or dry mass and/or, in particular, in the activity of the protease of interest to be achieved. Furthermore, the fermentation can also be designed such that unwanted metabolic products are filtered out or neutralized by adding buffer or appropriate counterions. The produced protease can be harvested from the fermentation medium. Such a fermentation process is preferable to isolating the protease from the host cell, i.e., product preparation from the cell mass (dry mass), but requires the provision of suitable host cells or one or more suitable secretion markers or mechanisms and/or transport systems to ensure that the host cells secrete the protease into the fermentation medium. Without secretion, the protease can alternatively be isolated from the host cell, i.e., purified from the cell mass, e.g., by precipitation with ammonium sulfate or ethanol, or by chromatographic purification.

Alle vorstehend ausgeführten Sachverhalte können zu Verfahren kombiniert werden, um erfindungsgemäße Protease herzustellen. Ein weiterer Gegenstand der Erfindung ist ein Mittel, das dadurch gekennzeichnet ist, dass es eine erfindungsgemäße Protease wie hierin beschrieben enthält. Bevorzugt ist das Mittel ein Wasch- und Reinigungsmittel, insbesondere bleichmittelhaltige Wasch- und Reinigungsmittel, bevorzugt Maschinengeschirrspülmittel, besonders bevorzugte bleichmittelhaltige Maschinengeschirrspülmittel. All of the above-mentioned facts can be combined into processes for producing protease according to the invention. The invention further provides an agent characterized in that it contains a protease according to the invention as described herein. The agent is preferably a washing and cleaning agent, in particular a washing and cleaning agent containing bleach, preferably a dishwasher detergent, particularly preferably a dishwasher detergent containing bleach.

In bevorzugten Ausführungsformen werden erfindungsgemäße Proteasen in Wasch- oder Reinigungsmitteln, insbesondere Maschinengeschirrspülmitteln, eingesetzt, die mindestens eine Bleichmittelzubereitung enthalten. In preferred embodiments, proteases according to the invention are used in washing or cleaning agents, in particular dishwasher detergents, which contain at least one bleaching agent preparation.

In bevorzugten Ausführungsformen umfasst die Bleichmittelzubereitung ein Sauerstoffbleichmittel, das aus der aus Wasserstoffperoxid, Peroxomonosulfat-Salzen, Peroxodisulfatsalzen und Phthalimidoperoxohexansäure (PAP) bestehenden Gruppe ausgewählt ist, wobei der Gewichtsanteil des Sauerstoffbleichmittels am Gesamtgewicht der Bleichmittelzubereitung vorzugsweise zwischen 0,1 und 50 Gew.-%, bevorzugt zwischen 0,2 und 35 Gew.-%, besonders bevorzugt zwischen 0,5 und 20 Gew.-% und insbesondere zwischen 1 ,0 und 10 Gew.-% beträgt. In preferred embodiments, the bleaching agent preparation comprises an oxygen bleaching agent selected from the group consisting of hydrogen peroxide, peroxomonosulfate salts, peroxodisulfate salts and phthalimidoperoxohexanoic acid (PAP), wherein the weight fraction of the oxygen bleaching agent in the total weight of the bleaching agent preparation is preferably between 0.1 and 50 wt.%, preferably between 0.2 and 35 wt.%, particularly preferably between 0.5 and 20 wt.% and in particular between 1.0 and 10 wt.%.

In bevorzugten Ausführungsformen umfasst die Bleichmittelzubereitung ein Oxidationsmittel. In bevorzugten Ausführungsformen ist das Oxidationsmittel bevorzugt ausgewählt aus Chlordioxid, Calciumhypochlorit, Kaliumhypochlorit, Natriumhypochlorit. In besonders bevorzugten Ausführungsformen umfasst die Bleichmittelzubereitung als Oxidationsmittel Natriumhypochlorid. In bevorzugten Ausführungsformen enthält die Bleichmittelzusammensetzung das mindestens eine Oxidationsmittel, bevorzugt das Alkalimetallhypochlorit, insbesondere das Natriumhypochlorit, in Mengen von 0,1 bis 8,0 Gew.-%, bevorzugt in 0,15 bis 3,0 Gew.-%, und stärker bevorzugt in 0,2 bis 1 ,0 Gew.-%, bezogen auf das Gesamtgewicht der Bleichmittelzubereitung. In preferred embodiments, the bleaching agent preparation comprises an oxidizing agent. In preferred embodiments, the oxidizing agent is preferably selected from chlorine dioxide, calcium hypochlorite, potassium hypochlorite, sodium hypochlorite. In particularly preferred embodiments, the bleaching agent preparation comprises sodium hypochlorite as oxidizing agent. In preferred embodiments, the bleaching agent composition contains the at least one oxidizing agent, preferably the alkali metal hypochlorite, in particular sodium hypochlorite, in amounts of 0.1 to 8.0 wt. %, preferably 0.15 to 3.0 wt. %, and more preferably 0.2 to 1.0 wt. %, based on the total weight of the bleaching agent preparation.

Unter den als Bleichmittel dienenden, in Wasser H2O2 liefernden Verbindungen haben das Natriumpercarbonat, das Natriumperborattetrahydrat und das Natriumperboratmonohydrat besondere Bedeutung. Weitere brauchbare Bleichmittel sind z.B. Peroxypyrophosphate, Citratperhydrate sowie H2O2 liefernde persaure Salze oder Persäuren, wie Perbenzoate, Peroxophthalate, Diperazelainsäure, Phthaloiminopersäure oder Diperdodecandisäure. Weiterhin können auch Bleichmittel aus der Gruppe der organischen Bleichmittel eingesetzt werden. Typische organische Bleichmittel sind die Diacylperoxide, wie z.B. Dibenzoylperoxid. Weitere typische organische Bleichmittel sind die Peroxysäuren, wobei als Beispiele besonders die Alkylperoxysäuren und die Arylperoxysäuren genannt werden. Among the compounds used as bleaching agents that yield H2O2 in water, sodium percarbonate, sodium perborate tetrahydrate, and sodium perborate monohydrate are particularly important. Other useful bleaching agents include peroxypyrophosphates, citrate perhydrates, and H2O2-yielding peracidic salts or peracids, such as perbenzoates, peroxophthalates, diperazelaic acid, phthaloiminoperacid, or diperdodecanedioic acid. Furthermore, bleaching agents from the group of organic bleaching agents can also be used. Typical organic bleaching agents are diacyl peroxides, such as dibenzoyl peroxide. Other typical organic bleaching agents are peroxyacids, with alkyl peroxyacids and aryl peroxyacids being particularly mentioned as examples.

In bevorzugten Ausführungsformen umfasst das Wasch- oder Reinigungsmittel, insbesondere Maschinengeschirrspülmittel, mindestens einen Bleichkatalysator aus der Gruppe der Übergangsmetallkatalysatoren. Bei diesen Stoffen handelt es sich vorzugsweise um bleichverstärkende Übergangsmetallsalze bzw. Übergangsmetallkomplexe wie z.B. Mn-, Fe-, Co-, Ru- oder Mo-Salenkomplexe oder -carbonylkomplexe. Auch Mn-, Fe-, Co-, Ru-, Mo-, Ti-, V- und Cu- Komplexe mit N-haltigen Tripod-Liganden sowie Co-, Fe-, Cu- und Ru-Amminkomplexe sind als Bleichkatalysatoren verwendbar. Mit besonderem Vorzug werden Komplexe des Mangans in der Oxidationsstufe II, III, IV oder IV eingesetzt, die vorzugsweise einen oder mehrere makrocyclische(n) Ligand(en) mit den Donorfunktionen N, NR, PR, O und/oder S enthalten. Vorzugsweise werden Liganden eingesetzt, die Stickstoff-Donorfunktionen aufweisen. Dabei ist es besonders bevorzugt, Bleichkatalysator(en) in den erfindungsgemäßen Mitteln einzusetzen, welche als makromolekularen Liganden 1 ,4,7-Trimethyl-1 ,4,7-triazacyclononan (Me-TACN), 1 ,4,7-Triazacyclononan (TACN), 1 ,5,9- Trimethyl-1 ,5,9-triazacyclododecan (Me-TACD), 2-Methyl-1 ,4,7-trimethyl-1 ,4,7-triazacyclononan (Me/Me-TACN) und/oder 2-Methyl-1 ,4,7-triazacyclononan (Me/TACN) enthalten. Bevorzugt beträgt der Gewichtsanteil des Bleichkatalysators am Gesamtgewicht des Wasch- oder Reinigungsmittels 0,001 bis 2,0 Gew.-%, bevorzugt 0,001 bis 1 ,0 Gew.-% und insbesondere 0,001 bis 0,5 Gew.-%. In preferred embodiments, the washing or cleaning agent, in particular automatic dishwashing agent, comprises at least one bleach catalyst from the group of transition metal catalysts. These substances are preferably bleach-enhancing transition metal salts or transition metal complexes, such as Mn, Fe, Co, Ru, or Mo salen complexes or carbonyl complexes. Mn, Fe, Co, Ru, Mo, Ti, V, and Cu complexes with N-containing tripod ligands, as well as Co, Fe, Cu, and Ru ammine complexes, can also be used as bleach catalysts. Particular preference is given to using complexes of manganese in oxidation state II, III, IV, or IV, which preferably contain one or more macrocyclic ligands with the donor functions N, NR, PR, O, and/or S. Preference is given to using ligands that have nitrogen donor functions. It is particularly preferred To use bleach catalyst(s) in the agents according to the invention which contain 1,4,7-trimethyl-1,4,7-triazacyclononane (Me-TACN), 1,4,7-triazacyclononane (TACN), 1,5,9-trimethyl-1,5,9-triazacyclododecane (Me-TACD), 2-methyl-1,4,7-trimethyl-1,4,7-triazacyclononane (Me/Me-TACN) and/or 2-methyl-1,4,7-triazacyclononane (Me/TACN) as macromolecular ligands. The weight fraction of the bleach catalyst in the total weight of the washing or cleaning agent is preferably 0.001 to 2.0 wt.%, preferably 0.001 to 1.0 wt.% and in particular 0.001 to 0.5 wt.%.

Erfindungsgemäße Maschinengeschirrspülmittel können ferner Bleichaktivatoren enthalten, z.B. um beim Reinigen bei Temperaturen von 60°C und darunter eine verbesserte Bleichwirkung zu erreichen. Als Bleichaktivatoren können Verbindungen, die unter Perhydrolysebedingungen aliphatische Peroxocarbonsäuren mit vorzugsweise 1 bis 10 C-Atomen, insbesondere 2 bis 4 C- Atomen, und/oder ggf. substituierte Perbenzoesäure ergeben, eingesetzt werden. Geeignet sind Substanzen, die O- und/oder N-Acylgruppen der genannten C-Atomzahl und/oder ggf. substituierte Benzoylgruppen tragen. Bevorzugt werden mehrfach acylierte Alkylendiamine, wobei sich Tetraacetylethylendiamin (TAED) als besonders geeignet erwiesen hat. Diese Bleichaktivatoren, insbesondere TAED, werden vorzugsweise in Mengen von 0,1 bis 10 Gew.-%, insbesondere 0,1 bis 8 Gew.-%, besonders 2 bis 8 Gew.-% und besonders bevorzugt 2 bis 6 Gew.-%, bezogen auf das Gesamtgewicht des Mittels, eingesetzt. Dishwashing detergents according to the invention may further contain bleach activators, e.g., to achieve an improved bleaching effect when cleaning at temperatures of 60°C and below. Compounds that, under perhydrolysis conditions, yield aliphatic peroxocarboxylic acids having preferably 1 to 10 carbon atoms, in particular 2 to 4 carbon atoms, and/or optionally substituted perbenzoic acid, can be used as bleach activators. Suitable substances are those that carry O- and/or N-acyl groups with the stated number of carbon atoms and/or optionally substituted benzoyl groups. Polyacylated alkylenediamines are preferred, with tetraacetylethylenediamine (TAED) having proven particularly suitable. These bleach activators, in particular TAED, are preferably used in amounts of 0.1 to 10 wt.%, in particular 0.1 to 8 wt.%, particularly 2 to 8 wt.% and particularly preferably 2 to 6 wt.%, based on the total weight of the agent.

Bevorzugte Ausführungsformen betreffen Wasch- oder Reinigungsmittel, insbesondere Maschinengeschirrspülmittel, die jeweils bezogen auf das Gesamtgewicht des Mittels umfassen: Preferred embodiments relate to washing or cleaning agents, in particular dishwasher detergents, which each comprise, based on the total weight of the agent:

(A) mindestens eine erfindungsgemäße Protease, vorzugsweise in einer Menge von 1 x 10-8 bis 10 Gew.-% und zunehmend bevorzugt von 0,00001 bis 2 Gew.-%, 0,001 bis 1 Gew.-%, 0,007 bis 0,8 Gew.-%, 0,025 bis 0,5 Gew.-% oder 0,04 bis 0,38 Gew.-%, bezogen auf aktives Protein, (A) at least one protease according to the invention, preferably in an amount of 1 x 10 -8 to 10 wt.% and increasingly preferably from 0.00001 to 2 wt.%, 0.001 to 1 wt.%, 0.007 to 0.8 wt.%, 0.025 to 0.5 wt.% or 0.04 to 0.38 wt.%, based on active protein,

(B) mindestens eine Bleichmittelzubereitung, vorzugsweise in einer Menge von 2 bis 30 Gew.-% und zunehmend bevorzugt von 4 bis 25 Gew.-%, 5 bis 20 Gew.-% oder 6 bis 15 Gew.-%, (B) at least one bleaching agent preparation, preferably in an amount of 2 to 30 wt.% and increasingly preferably 4 to 25 wt.%, 5 to 20 wt.% or 6 to 15 wt.%,

(C) optional mindestens ein Bleichkatalysator, vorzugsweise in einer Menge von 0,001 bis 2,0 Gew.-% und zunehmend bevorzugt von 0,001 bis 1 ,0 Gew.-% oder 0,001 bis 0,5 Gew.-%, und(C) optionally at least one bleach catalyst, preferably in an amount of 0.001 to 2.0 wt.% and increasingly preferably from 0.001 to 1.0 wt.% or 0.001 to 0.5 wt.%, and

(D) optional mindestens einen Bleichaktivator, vorzugsweise in einer Menge von 0,1 bis 10 Gew.-% und zunehmend bevorzugt von 0,1 bis 8 Gew.-%, 2 bis 8 Gew.-% oder 2 bis 6 Gew.-%. (D) optionally at least one bleach activator, preferably in an amount of from 0.1 to 10% by weight and increasingly preferably from 0.1 to 8% by weight, 2 to 8% by weight or 2 to 6% by weight.

Bevorzugte Ausführungsformen betreffen Wasch- oder Reinigungsmittel, insbesondere Maschinengeschirrspülmittel, die jeweils bezogen auf das Gesamtgewicht des Mittels umfassen: Preferred embodiments relate to washing or cleaning agents, in particular dishwasher detergents, which each comprise, based on the total weight of the agent:

(A) mindestens eine erfindungsgemäße Protease, vorzugsweise in einer Menge von 1 x 10-8 bis 10 Gew.-% und zunehmend bevorzugt von 0,00001 bis 2 Gew.-%, 0,001 bis 1 Gew.-%, 0,007 bis 0,8 Gew.-%, 0,025 bis 0,5 Gew.-% oder 0,04 bis 0,38 Gew.-%, bezogen auf aktives Protein, und(A) at least one protease according to the invention, preferably in an amount of 1 x 10 -8 to 10 wt.% and increasingly preferably from 0.00001 to 2 wt.%, 0.001 to 1 wt.%, 0.007 to 0.8 wt.%, 0.025 to 0.5 wt.% or 0.04 to 0.38 wt.%, based on active protein, and

(B) mindestens eine Bleichmittelzubereitung, vorzugsweise in einer Menge von 2 bis 30 Gew.-% und zunehmend bevorzugt von 4 bis 25 Gew.-%, 5 bis 20 Gew.-% oder 6 bis 15 Gew.-%. (B) at least one bleaching agent preparation, preferably in an amount of 2 to 30 wt% and increasingly preferably 4 to 25 wt%, 5 to 20 wt% or 6 to 15 wt%.

Bevorzugte Ausführungsformen betreffen Wasch- oder Reinigungsmittel, insbesondere Maschinengeschirrspülmittel, die jeweils bezogen auf das Gesamtgewicht des Mittels umfassen: Preferred embodiments relate to washing or cleaning agents, in particular dishwasher detergents, which each comprise, based on the total weight of the agent:

(A) mindestens eine erfindungsgemäße Protease, vorzugsweise in einer Menge von 1 x 10-8 bis 10 Gew.-% und zunehmend bevorzugt von 0,00001 bis 2 Gew.-%, 0,001 bis 1 Gew.-%, 0,007 bis 0,8 Gew.-%, 0,025 bis 0,5 Gew.-% oder 0,04 bis 0,38 Gew.-%, bezogen auf aktives Protein, (B) mindestens eine Bleichmittelzubereitung, vorzugsweise in einer Menge von 2 bis 30 Gew.-% und zunehmend bevorzugt von 4 bis 25 Gew.-%, 5 bis 20 Gew.-% oder 6 bis 15 Gew.-%, (A) at least one protease according to the invention, preferably in an amount of 1 x 10 -8 to 10 wt.% and increasingly preferably from 0.00001 to 2 wt.%, 0.001 to 1 wt.%, 0.007 to 0.8 wt.%, 0.025 to 0.5 wt.% or 0.04 to 0.38 wt.%, based on active protein, (B) at least one bleaching agent preparation, preferably in an amount of 2 to 30 wt.% and increasingly preferably 4 to 25 wt.%, 5 to 20 wt.% or 6 to 15 wt.%,

(C) mindestens ein Bleichkatalysator, vorzugsweise in einer Menge von 0,001 bis 2,0 Gew.-% und zunehmend bevorzugt von 0,001 bis 1 ,0 Gew.-% oder 0,001 bis 0,5 Gew.-%, und (C) at least one bleach catalyst, preferably in an amount of 0.001 to 2.0 wt.% and increasingly preferably from 0.001 to 1.0 wt.% or 0.001 to 0.5 wt.%, and

(D) mindestens einen Bleichaktivator, vorzugsweise in einer Menge von 0,1 bis 10 Gew.-% und zunehmend bevorzugt von 0,1 bis 8 Gew.-%, 2 bis 8 Gew.-% oder 2 bis 6 Gew.-%. (D) at least one bleach activator, preferably in an amount of from 0.1 to 10% by weight and increasingly preferably from 0.1 to 8% by weight, 2 to 8% by weight or 2 to 6% by weight.

In bevorzugten Ausführungsformen wird die erfindungsgemäße Protease in Mitteln eingesetzt, die im Wesentlichen frei von borhaltigen Verbindungen sind. "Im Wesentlichen frei von borhaltigen Verbindungen" bedeutet in diesem Zusammenhang, dass die erfindungsgemäßen Mittel weniger als 2 Gew.-%, vorzugsweise weniger als 1 Gew.-%, weiter bevorzugt weniger als 0,5 Gew.-% und besonders bevorzugt weniger als 0,1 Gew.-%, borhaltige Verbindungen, bezogen auf das Gesamtgewicht des Mittels, enthalten. In ganz besonders bevorzugten Ausführungsformen sind die erfindungsgemäßen Wasch- und Reinigungsmittel frei von borhaltigen Verbindungen, d.h. sie enthalten insbesondere keine Borsäure und/oder Phenylboronsäurederivate. In preferred embodiments, the protease according to the invention is used in agents that are essentially free of boron-containing compounds. "Essentially free of boron-containing compounds" in this context means that the agents according to the invention contain less than 2% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and particularly preferably less than 0.1% by weight, of boron-containing compounds, based on the total weight of the agent. In very particularly preferred embodiments, the washing and cleaning agents according to the invention are free of boron-containing compounds, i.e., they contain, in particular, no boric acid and/or phenylboronic acid derivatives.

In bevorzugten Ausführungsformen wird die erfindungsgemäße Protease in Mitteln eingesetzt, die im Wesentlichen frei von phosphonathaltigen Verbindungen sind. "Im Wesentlichen frei von phosphonathaltigen Verbindungen" bedeutet in diesem Zusammenhang, dass die erfindungsgemäßen Mittel weniger als 2 Gew.-%, vorzugsweise weniger als 1 Gew.-%, weiter bevorzugt weniger als 0,5 Gew.-% und besonders bevorzugt weniger als 0,1 Gew.-%, phosphonathaltige Verbindungen, bezogen auf das Gesamtgewicht des Mittels enthalten. In besonders bevorzugten Ausführungsformen sind diese Mittel frei von phosphonathaltigen Verbindungen. In preferred embodiments, the protease according to the invention is used in agents that are essentially free of phosphonate-containing compounds. "Essentially free of phosphonate-containing compounds" in this context means that the agents according to the invention contain less than 2% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and particularly preferably less than 0.1% by weight, of phosphonate-containing compounds, based on the total weight of the agent. In particularly preferred embodiments, these agents are free of phosphonate-containing compounds.

In bevorzugten Ausführungsformen wird die erfindungsgemäße Protease in Mitteln eingesetzt, die im Wesentlichen frei von phosphathaltigen Verbindungen sind. "Im Wesentlichen frei von phosphathaltigen Verbindungen" bedeutet in diesem Zusammenhang, dass die erfindungsgemäßen Mittel weniger als 2 Gew.-%, vorzugsweise weniger als 1 Gew.-%, weiter bevorzugt weniger als 0,5 Gew.-% und besonders bevorzugt weniger als 0,1 Gew.-%, phosphathaltige Verbindungen, bezogen auf das Gesamtgewicht des Mittels enthalten. In besonders bevorzugten Ausführungsformen sind diese Mittel frei von phosphathaltigen Verbindungen. In preferred embodiments, the protease according to the invention is used in agents that are essentially free of phosphate-containing compounds. "Essentially free of phosphate-containing compounds" in this context means that the agents according to the invention contain less than 2% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and particularly preferably less than 0.1% by weight, of phosphate-containing compounds, based on the total weight of the agent. In particularly preferred embodiments, these agents are free of phosphate-containing compounds.

Unter einem Wasch- oder Reinigungsmittel sind erfindungsgemäß alle denkbaren Wasch- oder Reinigungsmittelarten zu verstehen, sowohl Konzentrate als auch unverdünnt anzuwendende Mittel, zum Einsatz im kommerziellen Maßstab, in der Waschmaschine oder bei der Handwäsche bzw. -reinigung. Dazu gehören z.B. Waschmittel für Textilien, Teppiche, oder Naturfasern, für die die Bezeichnung Waschmittel verwendet wird. Dazu gehören z.B. auch Geschirrspülmittel für Geschirrspülmaschinen (maschinelle Geschirrspülmittel) oder manuelle Geschirrspülmittel oder Reiniger für harte Oberflächen wie Metall, Glas, Porzellan, Keramik, Kacheln, Stein, lackierte Oberflächen, Kunststoffe, Holz oder Leder, für die die Bezeichnung Reinigungsmittel verwendet wird, also neben manuellen und maschinellen Geschirrspülmitteln z.B. auch Scheuermittel, Glasreiniger, WC-Duftspüler, usw. Zu den Wasch- und Reinigungsmittel im Rahmen der Erfindung zählen ferner Waschhilfsmittel, die bei der manuellen oder maschinellen Textilwäsche zum eigentlichen Waschmittel hinzudosiert werden, um eine weitere Wirkung zu erzielen. Ferner zählen zu Wasch- und Reinigungsmittel im Rahmen der Erfindung auch Textilvor- und Nachbehandlungsmittel, also solche Mittel, mit denen das Wäschestück vor der eigentlichen Wäsche in Kontakt gebracht wird, z.B. zum Anlösen hartnäckiger Verschmutzungen, und auch solche Mittel, die in einem der eigentlichen Textilwäsche nachgeschalteten Schritt dem Waschgut weitere wünschenswerte Eigenschaften wie angenehmen Griff, Knitterfreiheit oder geringe statische Aufladung verleihen. Zu letztgenannten Mittel werden u.a. die Weichspüler gerechnet. According to the invention, a washing or cleaning agent is understood to mean all conceivable types of washing or cleaning agents, both concentrated and undiluted, for use on a commercial scale, in a washing machine or for hand washing or cleaning. This includes, for example, washing agents for textiles, carpets, or natural fibers, for which the term washing agent is used. This also includes, for example, dishwashing detergents for dishwashers (machine dishwashing detergents) or manual dishwashing detergents or cleaners for hard surfaces such as metal, glass, porcelain, ceramics, tiles, stone, painted surfaces, plastics, wood, or leather, for which the term cleaning agent is used, i.e., in addition to manual and machine dishwashing detergents, scouring agents, glass cleaners, toilet air fresheners, etc. The washing and cleaning agents within the scope of the invention also include washing aids that are added to the actual washing agent during manual or machine textile washing to achieve an additional effect. Furthermore, washing and Within the scope of the invention, cleaning agents also include textile pre- and post-treatment agents, i.e., agents with which the laundry is brought into contact before the actual washing process, e.g., to loosen stubborn dirt, and also agents that, in a step following the actual textile washing process, impart further desirable properties to the laundry, such as a pleasant feel, crease resistance, or low static charge. Fabric softeners are considered to be among the latter agents.

Die erfindungsgemäßen Wasch- oder Reinigungsmittel, die als pulverförmige oder granuläre Feststoffe, in verdichteter oder nachverdichteter Teilchenform, als homogene Lösungen oder Suspensionen vorliegen können, können neben einer erfindungsgemäßen Protease alle bekannten und in derartigen Mitteln üblichen Inhaltsstoffe enthalten, wobei bevorzugt mindestens ein weiterer Inhaltsstoff in dem Mittel vorhanden ist. Die erfindungsgemäßen Mittel können insbesondere Tenside, Builder (Gerüststoffe), Polymere, Glaskorrosionsinhibitoren, Korrosionsinhibitoren, Bleichmittel wie Persauerstoffverbindungen, Bleichaktivatoren oder Bleichkatalysatoren enthalten. Ferner können sie wassermischbare organische Lösungsmittel, weitere Enzyme, Enzymstabilisatoren, Sequestrierungsmittel, Elektrolyte, pH-Regulatoren und/oder weitere Hilfsstoffe wie optische Aufheller, Vergrauungsinhibitoren, Farbübertragungsinhibitoren, Schaumregulatoren sowie Färb- und Duftstoffe sowie Kombinationen hiervon enthalten. Vorteilhafte Inhaltsstoffe erfindungsgemäßer Mittel sind offenbart in der internationalen Patentanmeldung WO 2009/121725, dort beginnend auf Seite 5, vorletzter Absatz, und endend auf Seite 13 nach dem zweiten Absatz. Auf diese Offenbarung wird ausdrücklich Bezug genommen und der dortige Offenbarungsgehalt in die vorliegende Patentanmeldung einbezogen. The washing or cleaning agents according to the invention, which can be in the form of powdered or granular solids, in compacted or recompacted particle form, as homogeneous solutions or suspensions, can contain, in addition to a protease according to the invention, all known ingredients customary in such agents, with at least one further ingredient preferably being present in the agent. The agents according to the invention can contain, in particular, surfactants, builders, polymers, glass corrosion inhibitors, corrosion inhibitors, bleaching agents such as peroxygen compounds, bleach activators or bleach catalysts. They can also contain water-miscible organic solvents, other enzymes, enzyme stabilizers, sequestering agents, electrolytes, pH regulators and/or other auxiliaries such as optical brighteners, graying inhibitors, dye transfer inhibitors, foam regulators, dyes and fragrances, and combinations thereof. Advantageous ingredients of the compositions according to the invention are disclosed in the international patent application WO 2009/121725, beginning on page 5, penultimate paragraph, and ending on page 13 after the second paragraph. This disclosure is expressly incorporated by reference, and the disclosure content therein is incorporated into the present patent application.

Ein erfindungsgemäßes Mittel enthält die erfindungsgemäße Protease vorteilhafterweise in einer Menge von 2 pg bis 20 mg, vorzugsweise von 5 pg bis 17,5 mg, besonders bevorzugt von 20 pg bis 15 mg und ganz besonders bevorzugt von 50 pg bis 10 mg pro g des Mittels. In verschiedenen Ausführungsformen beträgt die Konzentration der hierin beschriebenen Protease (aktives Enzym) in dem Mittel >0 bis 1 Gew.-%, vorzugsweise 0,0001 oder 0,001 bis 0,1 Gew.-% bezogen auf das Gesamtgewicht des Mittels oder der Zusammensetzung. An agent according to the invention advantageously contains the protease according to the invention in an amount of 2 pg to 20 mg, preferably 5 pg to 17.5 mg, particularly preferably 20 pg to 15 mg, and most preferably 50 pg to 10 mg per g of the agent. In various embodiments, the concentration of the protease described herein (active enzyme) in the agent is >0 to 1 wt.%, preferably 0.0001 or 0.001 to 0.1 wt.%, based on the total weight of the agent or composition.

Ein erfindungsgemäßes Mittel enthält die Protease zunehmend bevorzugt in einer Menge von 1 x 10-8 bis 5 Gew.-%, von 0,0001 bis 1 Gew.-%, von 0,0005 bis 0,5 Gew.-%, von 0,001 bis 0,1 Gew.-%, jeweils bezogen auf aktives Protein und bezogen auf das Gesamtgewicht des Waschmittels. An agent according to the invention increasingly preferably contains the protease in an amount of 1 x 10 -8 to 5 wt.%, from 0.0001 to 1 wt.%, from 0.0005 to 0.5 wt.%, from 0.001 to 0.1 wt.%, in each case based on active protein and based on the total weight of the detergent.

Die Ausführungsformen der vorliegenden Erfindung umfassen alle festen, pulverförmigen, flüssigen, gelförmigen oder pastösen Darreichungsformen erfindungsgemäßer Mittel, die ggf. auch aus mehreren Phasen bestehen können sowie in komprimierter oder nicht komprimierter Form vorliegen können. Das Mittel kann als rieselfähiges Pulver vorliegen, insbesondere mit einem Schüttgewicht von 300 g/l bis 1200 g/l, insbesondere 500 g/l bis 900 g/l oder 600 g/l bis 850 g/l. Zu den festen Darreichungsformen des Mittels zählen ferner Extrudate, Granulate, Tabletten oder Pouches. Alternativ kann das Mittel auch flüssig, gelförmig oder pastös sein, z.B. in Form eines nichtwässrigen Flüssigwaschmittels oder einer nicht-wässrigen Paste oder in Form eines wässrigen Flüssigwaschmittels oder einer wasserhaltigen Paste. Flüssige Mittel sind generell bevorzugt. Weiterhin kann das Mittel als Einkomponentensystem vorliegen. Solche Mittel bestehen aus einer Phase. Alternativ kann ein Mittel auch aus mehreren Phasen bestehen. Ein solches Mittel ist demnach in mehrere Komponenten aufgeteilt. The embodiments of the present invention encompass all solid, powdered, liquid, gel-like, or pasty dosage forms of agents according to the invention, which may optionally also consist of several phases and may be present in compressed or uncompressed form. The agent may be in the form of a free-flowing powder, in particular with a bulk density of 300 g/l to 1200 g/l, in particular 500 g/l to 900 g/l or 600 g/l to 850 g/l. Solid dosage forms of the agent also include extrudates, granules, tablets, or pouches. Alternatively, the agent may also be liquid, gel-like, or pasty, e.g., in the form of a non-aqueous liquid detergent or a non-aqueous paste, or in the form of an aqueous liquid detergent or a water-containing paste. Liquid agents are generally preferred. Furthermore, the agent may be in the form of a one-component system. Such agents consist of a Phase. Alternatively, a remedy can also consist of several phases. Such a remedy is therefore divided into several components.

Die erfindungsgemäßen Proteasen werden bevorzugt in Maschinengeschirrspülmitteln, insbesondere bleichmittelhaltigen Maschinengeschirrspülmitteln, zum Reinigen von harten Oberflächen, insbesondere Geschirr, eingesetzt. The proteases according to the invention are preferably used in automatic dishwashing detergents, in particular automatic dishwashing detergents containing bleach, for cleaning hard surfaces, in particular dishes.

Erfindungsgemäße Wasch- oder Reinigungsmittel können ausschließlich eine erfindungsgemäße Protease enthalten. Alternativ können sie auch weitere hydrolytische Enzyme oder andere Enzyme in einer für die Wirksamkeit des Mittels zweckmäßigen Konzentration enthalten. Eine weitere Ausführungsform der Erfindung stellen somit Mittel dar, die ferner eines oder mehrere weitere Enzyme umfassen. Als weitere Enzyme bevorzugt einsetzbar sind alle Enzyme, die in dem erfindungsgemäßen Mittel eine katalytische Aktivität entfalten können, insbesondere eine Lipase, Amylase, Cellulase, Hemicellulase, Mannanase, Tannase, Xylanase, Xanthanase, Xyloglucanase, ß- Glucosidase, Pektinase, Carrageenase, Perhydrolase, Oxidase, Oxidoreduktase oder andere - von den erfindungsgemäßen Proteasen unterscheidbare - Protease, sowie deren Gemische. Weitere Enzyme sind in dem Mittel vorteilhafterweise jeweils in einer Menge von 1 x 10-8 bis 5 Gew.-% bezogen auf aktives Protein enthalten. Zunehmend bevorzugt ist jedes weitere Enzym in einer Menge von 1 x 10-7 bis 3 Gew.-%, von 0,00001 bis 1 Gew.-%, von 0,00005 bis 0,5 Gew.-%, von 0,0001 bis 0,1 Gew.-% und besonders bevorzugt von 0,0001 bis 0,05 Gew.-% in erfindungsgemäßen Mitteln enthalten, bezogen auf aktives Protein. Besonders bevorzugt zeigen die Enzyme synergistische Reinigungsleistungen gegenüber bestimmten Anschmutzungen oder Flecken, d.h. die in dem Mittel enthaltenen Enzyme unterstützen sich in ihrer Reinigungsleistung gegenseitig. Ganz besonders bevorzugt liegt ein solcher Synergismus vor zwischen der erfindungsgemäß enthaltenen Protease und einem weiteren Enzym eines erfindungsgemäßen Mittels. Synergistische Effekte können nicht nur zwischen verschiedenen Enzymen, sondern auch zwischen einem oder mehreren Enzymen und weiteren Inhaltsstoffen des erfindungsgemäßen Mittels auftreten. Detergents or cleaning agents according to the invention can contain exclusively one protease according to the invention. Alternatively, they can also contain further hydrolytic enzymes or other enzymes in a concentration appropriate for the effectiveness of the agent. A further embodiment of the invention thus represents agents which further comprise one or more further enzymes. Preferably used further enzymes are all enzymes which can exhibit catalytic activity in the agent according to the invention, in particular a lipase, amylase, cellulase, hemicellulase, mannanase, tannase, xylanase, xanthanase, xyloglucanase, ß-glucosidase, pectinase, carrageenase, perhydrolase, oxidase, oxidoreductase or other proteases distinguishable from the proteases according to the invention, as well as mixtures thereof. Further enzymes are advantageously contained in the agent in an amount of 1 x 10 -8 to 5 wt.%, based on active protein. With increasing preference, each further enzyme is contained in agents according to the invention in an amount of 1 x 10 -7 to 3 wt.%, from 0.00001 to 1 wt.%, from 0.00005 to 0.5 wt.%, from 0.0001 to 0.1 wt.% and particularly preferably from 0.0001 to 0.05 wt.%, based on active protein. The enzymes particularly preferably display synergistic cleaning performance against certain soilings or stains, i.e. the enzymes contained in the agent mutually support each other in their cleaning performance. Such synergism very particularly preferably exists between the protease contained according to the invention and another enzyme in an agent according to the invention. Synergistic effects can occur not only between different enzymes, but also between one or more enzymes and other ingredients of the agent according to the invention.

Erfindungsgemäß bevorzugte Maschinengeschirrspülmittel weisen mindestens eine Protease und mindestens eine Amylase auf. Dishwashing detergents preferred according to the invention comprise at least one protease and at least one amylase.

Erfindungsgemäß bevorzugte Textilwaschmittel weisen mindestens eine Protease und mindestens eine Amylase auf. In einerweiteren bevorzugten Ausführungsform der Erfindung weisen Textilwaschmittel mindestens eine Protease und mindestens eine Cellulase auf. In einerweiteren bevorzugten Ausführungsform weisen Textilwaschmittel mindestens eine Protease und mindestens eine Lipase auf. In einerweiteren bevorzugten Ausführungsform weisen Textilwaschmittel mindestens eine Protease, mindestens eine Amylase und mindestens eine Lipase auf. In einer weiteren bevorzugten Ausführungsform weisen Textilwaschmittel mindestens eine Protease, mindestens eine Amylase und mindestens eine Cellulase auf. In einerweiteren bevorzugten Ausführungsform weisen Textilwaschmittel mindestens eine Protease, mindestens eine Amylase, mindestens eine Cellulase und mindestens eine Lipase auf. Textile detergents preferred according to the invention comprise at least one protease and at least one amylase. In a further preferred embodiment of the invention, textile detergents comprise at least one protease and at least one cellulase. In a further preferred embodiment, textile detergents comprise at least one protease and at least one lipase. In a further preferred embodiment, textile detergents comprise at least one protease, at least one amylase, and at least one lipase. In a further preferred embodiment, textile detergents comprise at least one protease, at least one amylase, and at least one cellulase. In a further preferred embodiment, textile detergents comprise at least one protease, at least one amylase, at least one cellulase, and at least one lipase.

Beispiele für Proteasen sind die Subtilisine BPN' aus Bacillus amyloliquefaciens und Carlsberg aus Bacillus licheniformis, die Protease PB92, die Subtilisine 147 und 309, die Protease aus Bacillus lentus, Subtilisin DY und die den Subtilasen, nicht mehr jedoch den Subtilisinen im engeren Sinne zuzuordnenden Enzyme Thermitase, Proteinase K und die Proteasen TW3 und TW7. Subtilisin Carlsberg ist in weiterentwickelter Form unter dem Handelsnamen Alcalase® von dem Unternehmen Novozymes erhältlich. Die Subtilisine 147 und 309 werden unter den Handelsnamen Esperase® bzw. Savinase® von dem Unternehmen Novozymes vertrieben. Von der Protease aus Bacillus lentus DSM 5483 leiten sich Protease- Varianten ab, beschrieben in z.B. WO 95/23221 , WO 92/21760 WO 2013/060621 und EP 3660151. Weitere brauchbare Proteasen sind z.B. die unter den Handelsnamen Durazym®, Relase®, Everlase®, Nafizym®, Kannase®, Progress Uno 101 L® und Ovozyme® von dem Unternehmen Novozymes, die unter den Handelsnamen, Purafect®, Purafect® OxP, Purafect® Prime, Excellase®, Properase®, Preferenz P100® und Preferenz P300® von dem Unternehmen Danisco/DuPont, das unter dem Handelsnamen Lavergy pro 104 LS® von dem Unternehmen BASF, das unter dem Handelsnamen Protosol® von dem Unternehmen Advanced Biochemicals Ltd., das unter dem Handelsnamen Wuxi® von dem Unternehmen Wuxi Snyder Bioproducts Ltd., die unter den Handelsnamen Proleather® und Protease P® von dem Unternehmen Amano Pharmaceuticals Ltd., und das unter der Bezeichnung Proteinase K-16 von dem Unternehmen Kao Corp, erhältlichen Enzyme. Besonders bevorzugt eingesetzt werden auch die Proteasen aus Bacillus gibsonii und Bacillus pumilus, die offenbart sind in WO 2008/086916, WO 2007/131656, WO 2017/215925, WO 2021/175696 und WO 2021/175697. Weitere verwendbare Proteasen sind diejenigen, die in den Mikroorganismen Stenotrophomonas maltophilia, insbesondere Stenotrophomonas maltophilia K279a, Bacillus intermedius sowie Bacillus sphaericus natürlicherweise vorhanden sind. Examples of proteases are the subtilisins BPN' from Bacillus amyloliquefaciens and Carlsberg from Bacillus licheniformis, the protease PB92, the subtilisins 147 and 309, the protease from Bacillus lentus, subtilisin DY and the subtilases, but no longer the subtilisins in the narrower sense The enzymes attributable to thermitase, proteinase K, and the proteases TW3 and TW7. Subtilisin Carlsberg is available in a further developed form under the trade name Alcalase® from Novozymes. Subtilisins 147 and 309 are marketed by Novozymes under the trade names Esperase® and Savinase®, respectively. Protease variants are derived from the protease from Bacillus lentus DSM 5483, described in e.g. WO 95/23221, WO 92/21760, WO 2013/060621 and EP 3660151. Other useful proteases are, for example, those sold under the trade names Durazym®, Relase®, Everlase®, Nafizym®, Kannase®, Progress Uno 101 L® and Ovozyme® by Novozymes, those sold under the trade names Purafect®, Purafect® OxP, Purafect® Prime, Excellase®, Properase®, Preferenz P100® and Preferenz P300® by Danisco/DuPont, those sold under the trade name Lavergy pro 104 LS® by BASF, those sold under the trade name Protosol® by Advanced Biochemicals Ltd., those sold under the trade name Wuxi® from Wuxi Snyder Bioproducts Ltd., the enzymes available under the trade names Proleather® and Protease P® from Amano Pharmaceuticals Ltd., and the enzyme available under the name Proteinase K-16 from Kao Corp. The proteases from Bacillus gibsonii and Bacillus pumilus, which are disclosed in WO 2008/086916, WO 2007/131656, WO 2017/215925, WO 2021/175696 and WO 2021/175697, are also particularly preferably used. Other usable proteases are those that are naturally present in the microorganisms Stenotrophomonas maltophilia, in particular Stenotrophomonas maltophilia K279a, Bacillus intermedius and Bacillus sphaericus.

Beispiele für Amylasen sind die a-Amylasen aus Bacillus licheniformis, Bacillus amyloliquefaciens oder Bacillus stearothermophilus sowie insbesondere auch deren für den Einsatz in Wasch- oder Reinigungsmitteln verbesserte Weiterentwicklungen. Das Enzym aus Bacillus licheniformis ist von dem Unternehmen Novozymes unter dem Namen Termamyl® und von dem Unternehmen Danisco/DuPont unter dem Namen Purastar® ST erhältlich. Weiterentwicklungsprodukte dieser a- Amylase sind unter den Handelsnamen Duramyl® und Termamyl® ultra (beide von Novozymes), Purastar® OxAm (Danisco/DuPont) und Keistase® (Daiwa Seiko Inc.) erhältlich. Die a-Amylase von Bacillus amyloliquefaciens wird von dem Unternehmen Novozymes unter dem Namen BAN® vertrieben, und abgeleitete Varianten von der a-Amylase aus Bacillus stearothermophilus unter den Namen BSG® und Novamyl®, ebenfalls von dem Unternehmen Novozymes. Des Weiteren sind für diesen Zweck die a-Amylase aus Bacillus sp. A 7-7 (DSM 12368) und die Cyclodextrin- Glucanotransferase (CGTase) aus Bacillus agaradherens (DSM 9948) hervorzuheben. Ebenso sind Fusionsprodukte aller genannten Moleküle einsetzbar. Darüber hinaus sind die unter den Handelsnamen Fungamyl® von dem Unternehmen Novozymes erhältlichen Weiterentwicklungen der a-Amylase aus Aspergillus niger und A. oryzae geeignet. Weitere vorteilhaft einsetzbare Handelsprodukte sind z.B. die Amylase-LT® und Stainzyme® oder Stainzyme® ultra bzw. Stainzyme® plus sowie Amplify™ 12L, Amplify Prime™ 120L oder Amplify Prime™ 100L, letztere ebenfalls von dem Unternehmen Novozymes, sowie die PREFERENZ S® Serie von dem Unternehmen Danisco/DuPont, umfassend z.B. PREFERENZ S100®, PREFERENZ S1000® oder PREFERENZ S210®. Auch durch Punktmutationen erhältliche Varianten dieser Enzyme können erfindungsgemäß eingesetzt werden. Geeignete Cellulasen umfassen solche bakterieller oder pilzlicher Herkunft. Chemisch modifizierte oder proteintechnisch veränderte Mutanten sind eingeschlossen. Geeignete Cellulasen sind Cellulasen aus den Gattungen Bacillus, Pseudomonas, Humicola, Fusarium, Thielavia, Acremonium, z. B. die Pilzcellulasen aus Humicola insolens, Myceliophthora thermophila und Fusarium oxysporum, die in US 4435307, US 5648263, US 5691178, US 5776757 und WO 89/09259 offenbart sind. Besonders geeignete Cellulasen sind die alkalischen oder neutralen Cellulasen mit farbpflegenden Eigenschaften. Beispiele für solche Cellulasen sind Cellulasen, die in EP 0495257, EP 0531372, WO 96/11262, WO 96/29397 und WO 98/08940 beschrieben sind. Beispiele für Cellulasen mit Endo-1 ,4-Glucanase-Aktivität (EC 3.2.1 .4) sind in WO 2002/099091 beschrieben, z.B. solche mit einer Sequenz von mindestens 97% Identität zu der Aminosäuresequenz der Positionen 1 bis 773 von SEQ ID NO:2 der WO 2002/099091. Ein weiteres Beispiel kann eine GH44-Xyloglucanase umfassen, z.B. ein Xyloglucanase-Enzym mit einer Sequenz von mindestens 60% Identität zu den Positionen 40 bis 559 der SEQ ID NO:2 der WO 2001/062903. Zu den kommerziell verfügbaren Cellulasen gehören Celluzyme™, Carezyme™, Carezyme Premium™, Celluclean™ (z.B. Celluclean™ 5000L ans Celluclean™ 4000T), Celluclean Classic™, Cellusoft™, Endolase®, Renozyme® und Whitezyme™ (Novozymes A/S), Clazinase™ und Puradax HA™ (Genencor International Inc.), KAC-500(B)™ (Kao Corporation), Revitalenz™ 1000, Revitalenz™ 2000 und Revitalenz™ 3000 (DuPont), sowie Ecostone® und Biotouch® (AB Enzymes). Examples of amylases are the α-amylases from Bacillus licheniformis, Bacillus amyloliquefaciens or Bacillus stearothermophilus and, in particular, their further developments improved for use in detergents or cleaning agents. The enzyme from Bacillus licheniformis is available from Novozymes under the name Termamyl® and from Danisco/DuPont under the name Purastar® ST. Further developments of this α-amylase are available under the trade names Duramyl® and Termamyl® ultra (both from Novozymes), Purastar® OxAm (Danisco/DuPont) and Keistase® (Daiwa Seiko Inc.). The α-amylase from Bacillus amyloliquefaciens is marketed by Novozymes under the name BAN®, and derived variants of the α-amylase from Bacillus stearothermophilus under the names BSG® and Novamyl®, also from Novozymes. Other suitable enzymes for this purpose include α-amylase from Bacillus sp. A 7-7 (DSM 12368) and cyclodextrin glucanotransferase (CGTase) from Bacillus agaradherens (DSM 9948). Fusion products of all of these molecules can also be used. Furthermore, the further developments of α-amylase from Aspergillus niger and A. oryzae, available under the trade name Fungamyl® from Novozymes, are also suitable. Other commercial products that can be used advantageously include Amylase-LT® and Stainzyme® or Stainzyme® ultra or Stainzyme® plus, as well as Amplify™ 12L, Amplify Prime™ 120L, or Amplify Prime™ 100L, the latter also from Novozymes, and the PREFERENZ S® series from Danisco/DuPont, including PREFERENZ S100®, PREFERENZ S1000®, or PREFERENZ S210®. Variants of these enzymes obtainable through point mutations can also be used according to the invention. Suitable cellulases include those of bacterial or fungal origin. Chemically modified or protein-engineered mutants are also included. Suitable cellulases are cellulases from the genera Bacillus, Pseudomonas, Humicola, Fusarium, Thielavia, and Acremonium, e.g., the fungal cellulases from Humicola insolens, Myceliophthora thermophila, and Fusarium oxysporum, disclosed in US 4,435,307, US 5,648,263, US 5,691,178, US 5,776,757, and WO 89/09259. Particularly suitable cellulases are alkaline or neutral cellulases with color-care properties. Examples of such cellulases are cellulases described in EP 0495257, EP 0531372, WO 96/11262, WO 96/29397 and WO 98/08940. Examples of cellulases with endo-1,4-glucanase activity (EC 3.2.1.4) are described in WO 2002/099091, e.g., those with a sequence of at least 97% identity to the amino acid sequence of positions 1 to 773 of SEQ ID NO:2 of WO 2002/099091. Another example may comprise a GH44 xyloglucanase, e.g., a xyloglucanase enzyme with a sequence of at least 60% identity to positions 40 to 559 of SEQ ID NO:2 of WO 2001/062903. Commercially available cellulases include Celluzyme™, Carezyme™, Carezyme Premium™, Celluclean™ (e.g. Celluclean™ 5000L and Celluclean™ 4000T), Celluclean Classic™, Cellusoft™, Endolase®, Renozyme® and Whitezyme™ (Novozymes A/S), Clazinase™ and Puradax HA™ (Genencor International Inc.), KAC-500(B)™ (Kao Corporation), Revitalenz™ 1000, Revitalenz™ 2000 and Revitalenz™ 3000 (DuPont), as well as Ecostone® and Biotouch® (AB Enzymes).

Als weitere Enzyme einsetzbar sind z.B. Lipasen oder Cutinasen, insbesondere wegen ihrer Triglycerid-spaltenden Aktivitäten, aber auch, um aus geeigneten Vorstufen in situ Persäuren zu erzeugen. Geeignete Lipasen und Cutinasen sind solche bakteriellen oder pilzlichen Ursprungs. Chemisch modifizierte oder durch Proteinengineering erzeugte mutierte Enzyme sind eingeschlossen. Beispiele sind Lipase aus Thermomyces, z.B. aus T. lanuginosus (früher Humicola lanuginosa genannt), wie in EP 0258068 und EP 0305216 beschrieben, Cutinase aus Humicola, z.B. H. insolens (WO 96/13580), Lipase aus Stämmen von Pseudomonas (einige davon jetzt umbenannt in Burkholderia), z.B. P. alcaligenes oder P. pseudoalcaligenes, P. cepacia, P. sp. Stamm SD705, P. wisconsinensis, Streptomyces-Lipasen vom GDSL-Typ, Cutinase aus Magnaporthe grisea, Cutinase aus Pseudomonas mendocina, Lipase aus Thermobifida fusca, Lipase aus Geobacillus stearothermophilus, Lipase aus Bacillus subtilis und Lipase aus Streptomyces griseus und S. pristinaespiralis. Zu bevorzugten Lipasen gehören z.B. die ursprünglich aus Humicola lanuginosa (Thermomyces lanuginosus) erhältlichen bzw. daraus weiterentwickelten Lipasen, insbesondere solche mit einem oder mehreren der folgenden Aminosäureaustausche ausgehend von der genannten Lipase in den Positionen D96L, T213R und/oder N233R, besonders bevorzugt T213R und N233R. Zu den bevorzugten kommerziellen Lipaseprodukten gehören Lipolase™, Lipex™, Lipolex™ und Lipoclean™ (Novozymes A/S), Lumafast (Genencor/DuPont) und Lipomax (Gist-Brocades). Other enzymes that can be used include lipases or cutinases, particularly because of their triglyceride-cleaving activities, but also to generate peracids from suitable precursors in situ. Suitable lipases and cutinases are those of bacterial or fungal origin. Chemically modified or mutated enzymes produced by protein engineering are included. Examples are lipase from Thermomyces, e.g. from T. lanuginosus (formerly called Humicola lanuginosa), as described in EP 0258068 and EP 0305216, cutinase from Humicola, e.g. H. insolens (WO 96/13580), lipase from strains of Pseudomonas (some of which have now been renamed Burkholderia), e.g. P. alcaligenes or P. pseudoalcaligenes, P. cepacia, P. sp. Strain SD705, P. wisconsinensis, Streptomyces lipases of the GDSL type, cutinase from Magnaporthe grisea, cutinase from Pseudomonas mendocina, lipase from Thermobifida fusca, lipase from Geobacillus stearothermophilus, lipase from Bacillus subtilis, and lipase from Streptomyces griseus and S. pristinaespiralis. Preferred lipases include, for example, those originally obtainable from Humicola lanuginosa (Thermomyces lanuginosus) or developed therefrom, in particular those with one or more of the following amino acid substitutions starting from the aforementioned lipase at positions D96L, T213R, and/or N233R, particularly preferably T213R and N233R. Preferred commercial lipase products include Lipolase™, Lipex™, Lipolex™ and Lipoclean™ (Novozymes A/S), Lumafast (Genencor/DuPont) and Lipomax (Gist-Brocades).

Zur Erhöhung der bleichenden Wirkung können erfindungsgemäß Oxidoreduktasen, z.B. Oxidasen, Oxygenasen, Katalasen, Peroxidasen, wie Halo-, Chloro-, Bromo-, Lignin-, Glucose- oder Manganperoxidasen, Dioxygenasen oder Laccasen (Phenoloxidasen, Polyphenoloxidasen) eingesetzt werden. Vorteilhafterweise werden zusätzlich vorzugsweise organische, besonders bevorzugt aromatische, mit den Enzymen wechselwirkende Verbindungen zugegeben, um die Aktivität der betreffenden Oxidoreduktasen zu verstärken (Enhancer) oder um bei stark unterschiedlichen Redoxpotentialen zwischen den oxidierenden Enzymen und den Anschmutzungen den Elektronenfluss zu gewährleisten (Mediatoren). To increase the bleaching effect, oxidoreductases, e.g., oxidases, oxygenases, catalases, peroxidases, such as halo-, chloro-, bromo-, lignin-, glucose- or manganese peroxidases, dioxygenases or laccases (phenol oxidases, polyphenol oxidases) can be used according to the invention. Advantageously, organic compounds, particularly aromatic ones, which interact with the enzymes are additionally added in order to increase the activity of the oxidoreductases in question (enhancers) or to Redox potentials between the oxidizing enzymes and the soils to ensure the flow of electrons (mediators).

In den hierin beschriebenen Reinigungsmitteln können die einzusetzenden Enzyme ferner zusammen mit Begleitstoffen, etwa aus der Fermentation, konfektioniert sein. In flüssigen Formulierungen werden die Enzyme bevorzugt als Enzymflüssigformulierung(en) eingesetzt. In the cleaning agents described herein, the enzymes to be used can also be formulated together with accompanying substances, such as those from fermentation. In liquid formulations, the enzymes are preferably used as liquid enzyme formulation(s).

Die Enzyme werden in der Regel nicht in Form des reinen Proteins, sondern vielmehr in Form stabilisierter, lager- und transportfähiger Zubereitungen bereitgestellt. Zu diesen vorkonfektionierten Zubereitungen zählen z.B. die durch Granulation, Extrusion oder Lyophilisierung erhaltenen festen Präparationen oder, insbesondere bei flüssigen oder gelförmigen Mitteln, Lösungen der Enzyme, vorteilhafterweise möglichst konzentriert, wasserarm und/oder mit Stabilisatoren oder weiteren Hilfsmitteln versetzt. The enzymes are generally not provided in the form of pure protein, but rather in the form of stabilized, storable, and transportable preparations. These prefabricated preparations include, for example, solid preparations obtained by granulation, extrusion, or lyophilization or, particularly in the case of liquid or gel-like products, solutions of the enzymes, preferably as concentrated as possible, with little water content, and/or containing stabilizers or other additives.

Alternativ können die Enzyme sowohl für die feste als auch für die flüssige Darreichungsform verkapselt werden, z.B. durch Sprühtrocknung oder Extrusion der Enzymlösung zusammen mit einem vorzugsweise natürlichen Polymer oder in Form von Kapseln, z.B. solchen, bei denen die Enzyme wie in einem erstarrten Gel eingeschlossen sind oder in solchen vom Kern-Schale-Typ, bei dem ein enzymhaltiger Kern mit einer Wasser-, Luft- und/oder Chemikalien-undurchlässigen Schutzschicht überzogen ist. In aufgelagerten Schichten können zusätzlich weitere Wirkstoffe, z.B. Stabilisatoren, Emulgatoren, Pigmente, Bleich- oder Farbstoffe aufgebracht werden. Derartige Kapseln werden nach an sich bekannten Methoden, z.B. durch Schüttel- oder Rollgranulation oder in Fluid-bed-Prozessen aufgebracht. Vorteilhafterweise sind derartige Granulate, z.B. durch Aufbringen polymerer Filmbildner, staubarm und aufgrund der Beschichtung lagerstabil. Alternatively, the enzymes can be encapsulated for both solid and liquid dosage forms, e.g., by spray-drying or extrusion of the enzyme solution together with a preferably natural polymer, or in the form of capsules, e.g., those in which the enzymes are enclosed as if in a solidified gel, or in core-shell capsules, in which an enzyme-containing core is coated with a water-, air-, and/or chemical-impermeable protective layer. Additional active ingredients, e.g., stabilizers, emulsifiers, pigments, bleaching agents, or dyes, can be applied in superimposed layers. Such capsules are applied using conventional methods, e.g., by shaking or rolling granulation or in fluid-bed processes. Such granules, e.g., by applying polymeric film-forming agents, are advantageously low in dust and, due to the coating, are storage-stable.

Weiterhin ist es möglich, zwei oder mehrere Enzyme zusammen zu konfektionieren, so dass ein einzelnes Granulat mehrere Enzymaktivitäten aufweist. Furthermore, it is possible to package two or more enzymes together so that a single granulate has multiple enzyme activities.

Die Enzyme können auch in wasserlösliche Filme, wie sie z.B. bei der Konfektionierung von Wasch- und Reinigungsmitteln in Einheitsdosisform verwendet werden, eingebracht werden. Ein derartiger Film ermöglicht die Freisetzung der Enzyme nach Kontakt mit Wasser. Wie hierin verwendet, bezieht sich "wasserlöslich" auf eine Filmstruktur, die vorzugsweise vollständig wasserlöslich ist. Bevorzugt besteht ein solcher Film aus (vollständig oder teilweise hydrolysiertem) Polyvinylalkohol (PVA). The enzymes can also be incorporated into water-soluble films, such as those used in the packaging of unit-dose detergents and cleaning agents. Such a film allows the enzymes to be released upon contact with water. As used herein, "water-soluble" refers to a film structure that is preferably completely water-soluble. Preferably, such a film consists of (fully or partially hydrolyzed) polyvinyl alcohol (PVA).

Ein weiterer Erfindungsgegenstand ist ein Verfahren zur Reinigung von Textilien und/oder harten Oberflächen, insbesondere Geschirr, das dadurch gekennzeichnet ist, dass in mindestens einem Verfahrensschritt ein erfindungsgemäßes Mittel angewendet wird. In verschiedenen Ausführungsformen zeichnet sich das beschriebene Verfahren dadurch aus, dass die Protease bei einer Temperatur von etwa 0°C bis etwa 100°C, bevorzugt etwa 20°C bis etwa 75°C, weiter bevorzugt etwa 30°C bis etwa 60°C und besonders bevorzugt etwa 40°C bis etwa 55°C eingesetzt wird. The invention further relates to a method for cleaning textiles and/or hard surfaces, in particular tableware, which is characterized in that an agent according to the invention is used in at least one method step. In various embodiments, the described method is characterized in that the protease is used at a temperature of about 0°C to about 100°C, preferably about 20°C to about 75°C, more preferably about 30°C to about 60°C, and particularly preferably about 40°C to about 55°C.

Hierunter fallen sowohl manuelle als auch maschinelle Verfahren, wobei maschinelle Verfahren aufgrund ihrer präziseren Steuerbarkeit, was z.B. die eingesetzten Mengen und Einwirkzeiten angeht, bevorzugt sind. Verfahren zur Reinigung von Textilien zeichnen sich im Allgemeinen dadurch aus, dass in mehreren Verfahrensschritten verschiedene reinigungsaktive Substanzen auf das Reinigungsgut aufgebracht und nach der Einwirkzeit abgewaschen werden, oder dass das Reinigungsgut in sonstiger Weise mit einem Waschmittel oder einer Lösung oder Verdünnung dieses Mittels behandelt wird. This includes both manual and mechanical processes, with mechanical processes being preferred due to their more precise controllability, e.g., regarding the quantities used and exposure times. Textile cleaning processes are generally characterized by the fact that various cleaning-active substances are applied to the fabric in several process steps. applied to the item to be cleaned and washed off after the exposure time, or that the item to be cleaned is treated in any other way with a detergent or a solution or dilution of this agent.

Da erfindungsgemäße Proteasen natürlicherweise bereits eine hydrolytische Aktivität besitzen und diese auch in Medien entfalten, die sonst keine Reinigungskraft besitzen wie z.B. in bloßem Puffer, kann ein einzelner und/oder der einzige Schritt eines solchen Verfahrens darin bestehen, dass als einzige reinigungsaktive Komponente eine erfindungsgemäße Protease mit der Anschmutzung in Kontakt gebracht wird, bevorzugt in einer Pufferlösung oder in Wasser. Dies stellt eine weitere Ausführungsform dieses Erfindungsgegenstandes dar. Since proteases according to the invention naturally already possess hydrolytic activity and exhibit this activity even in media that otherwise have no cleaning power, such as in mere buffer, a single and/or the only step of such a process can consist of bringing a protease according to the invention into contact with the soil as the sole cleaning-active component, preferably in a buffer solution or in water. This represents a further embodiment of this subject matter of the invention.

Alternative Ausführungsformen dieses Erfindungsgegenstandes stellen auch Verfahren zur Behandlung von Textilrohstoffen oder zur Textilpflege dar, bei denen in wenigstens einem Verfahrensschritt eine erfindungsgemäße Protease aktiv wird. Hierunter sind Verfahren für Textilrohstoffe, Fasern oder Textilien mit natürlichen Bestandteilen bevorzugt, und ganz besonders für solche mit Wolle oder Seide. Alternative embodiments of this subject matter of the invention also include processes for treating textile raw materials or for textile care, in which a protease according to the invention is activated in at least one process step. Among these, processes for textile raw materials, fibers, or textiles with natural components are preferred, and especially for those containing wool or silk.

Ein weiterer Gegenstand der Erfindung betrifft ein Verfahren zur Reinigung von Textilien und/oder harten Oberflächen, insbesondere Geschirr, wobei in mindestens einem Verfahrensschritt ein Waschoder Reinigungsmittel, das eine erfindungsgemäße Protease, wie hierin beschrieben, enthält und/oder eine erfindungsgemäße Protease, wie hierin beschrieben, angewendet wird. Another subject of the invention relates to a method for cleaning textiles and/or hard surfaces, in particular dishes, wherein in at least one method step a washing or cleaning agent which contains a protease according to the invention as described herein and/or a protease according to the invention as described herein is used.

Schließlich erfasst die Erfindung auch die Verwendung erfindungsgemäßer Proteasen, wie hierin beschrieben, in Wasch- oder Reinigungsmitteln, insbesondere bleichmittelhaltigen Wasch- oder Reinigungsmitteln, bevorzugt Maschinengeschirrspülmitteln, besonders bevorzugt bleichmittelhaltigen Maschinengeschirrspülmitteln, zur Reinigung von Textilien und/oder harten Oberflächen, insbesondere Geschirr. Finally, the invention also encompasses the use of proteases according to the invention, as described herein, in washing or cleaning agents, in particular washing or cleaning agents containing bleach, preferably automatic dishwashing agents, particularly preferably automatic dishwashing agents containing bleach, for cleaning textiles and/or hard surfaces, in particular dishes.

Alle Sachverhalte, Gegenstände und Ausführungsformen, die für die erfindungsgemäße Protease und sie enthaltende Mittel beschrieben sind, sind auch auf diese Erfindungsgegenstände anwendbar. Daher wird an dieser Stelle ausdrücklich auf die Offenbarung an entsprechender Stelle verwiesen mit dem Hinweis, dass diese Offenbarung auch für die vorstehenden erfindungsgemäßen Verfahren und Verwendungen gilt. All facts, subject matters, and embodiments described for the protease according to the invention and agents containing it are also applicable to these subject matters of the invention. Therefore, express reference is made here to the disclosure at the appropriate point, with the note that this disclosure also applies to the above-mentioned methods and uses according to the invention.

BEISPIELE EXAMPLES

Beispiel 1 : Expression der Proteasevarianten Example 1 : Expression of protease variants

Die vorliegende Erfindung betrifft eine alkalische Protease vom Subtilisin Typ aus Bacillus gibsonii. Von dieser Protease (Wildtyp: Bacillus gibsonii Protease gemäß SEQ ID NO:1), wurden durch Zufallsmutagenese Varianten hergestellt, welche dann u.a. auf verbesserte Waschleistung und/oder verbesserte Enzymstabilität gescreent wurden. Auf diesem Weg wurde aus der oben genannten Wildtyp Protease (SEQ ID NO:1) durch Zufallsmutagenese und/oder Sättigungsmutagenese die hierin genannten Protease-Varianten generiert. Des Weiteren wurden einige Mutanten durch gezielte Erzeugung synthetischer Gene hergestellt. Die rekombinante Expression erfindungsgemäßer Protease-Varianten erfolgte gemäß in der Literatur beschriebener Verfahren (Vojcic et al., An efficient transformation method for Bacillus subtilis DB104, Appl Microbiol Biotechnol, 2012, 94 (2): 487-493). The present invention relates to an alkaline protease of the subtilisin type from Bacillus gibsonii. Variants of this protease (wild type: Bacillus gibsonii protease according to SEQ ID NO:1) were produced by random mutagenesis, which were then screened for, among other things, improved washing performance and/or improved enzyme stability. In this way, the protease variants mentioned herein were generated from the above-mentioned wild-type protease (SEQ ID NO:1) by random mutagenesis and/or saturation mutagenesis. Furthermore, some mutants were produced by targeted generation of synthetic genes. The recombinant expression of the protease variants according to the invention was carried out according to methods described in the literature (Vojcic et al., An efficient transformation method for Bacillus subtilis DB104, Appl Microbiol Biotechnol, 2012, 94 (2): 487-493).

Tabellel : Verwendete Proteasen:

Figure imgf000116_0001
Table: Proteases used:
Figure imgf000116_0001

Beispiel 2: Bestimmung der Proteaseaktivität Example 2: Determination of protease activity

Die Aktivität der Protease wird durch die Freisetzung des Chromophors para-Nitroanilin aus dem Substrat Succinyl Alanin-Alanin-Prolin-Phenylalanin-para-Nitroanilid (AAPFpNA; Bachem L-1400) bestimmt. Die Freisetzung des pNA verursacht eine Zunahme der Extinktion bei 410 nm, deren zeitlicher Verlauf ein Maß für die enzymatische Aktivität ist. The activity of the protease is determined by the release of the chromophore para-nitroaniline from the substrate succinyl alanine-alanine-proline-phenylalanine-para-nitroanilide (AAPFpNA; Bachem L-1400). The release of pNA causes an increase in absorbance at 410 nm, the time course of which is a measure of enzymatic activity.

Die Messung erfolgte bei einer Temperatur von 25°C, bei pH 8,6 und einer Wellenlänge von 410 nm. Die Messzeit betrug 5 min bei einem Messintervall von 20 bis 60 Sekunden. The measurement was carried out at a temperature of 25°C, at pH 8.6 and a wavelength of 410 nm. The measurement time was 5 min with a measurement interval of 20 to 60 seconds.

Messansatz: Measurement approach:

10 pL AAPF-Lösung (70 mg/mL) 10 pL AAPF solution (70 mg/mL)

1000 pL Tris/HCI (0,1 M; pH 8,6 mit 0,1% Brij 35) 1000 pL Tris/HCl (0.1 M; pH 8.6 with 0.1% Brij 35)

10 pL verdünnte Proteaselösung Kinetik erstellt über 5 min bei 25°C (410 nm) 10 pL diluted protease solution Kinetics generated over 5 min at 25°C (410 nm)

Eine Protease-Lösung, die unter diesen Bedingungen eine Absorptionsänderung von 0,500 OD bewirkt, hat nach vorliegender Bezeichnung eine Aktivität von 10 HPE pro ml (vgl. z.B. Schülein et al., Mol Gen Gent (1991) 227:137-143). A protease solution which causes an absorbance change of 0.500 OD under these conditions has, according to the current designation, an activity of 10 HPE per ml (cf. e.g. Schülein et al., Mol Gen Gent (1991) 227:137-143).

Beispiel 3: Bestimmung der Stabilität der Proteasen gegenüber Hypochlorit Example 3: Determination of the stability of proteases towards hypochlorite

Um die Stabilität erfindungsgemäßer Proteasen gegenüber Hypochlorit zu testen, wurden die in Tabelle 1 genannten Protease-Varianten in einer Waschflotte mit verschiedenen Aktivchlor- Konzentrationen versetzt und 30 min bei 30°C inkubiert. Die Reaktion wurde jeweils mit 2% Na-Sulfit (40 ml / 2ml) gestoppt und die Protease-Aktivität mittels AAPF (siehe Beispiel 2) bestimmt. To test the stability of proteases according to the invention to hypochlorite, the protease variants listed in Table 1 were added to a wash liquor containing various active chlorine concentrations and incubated for 30 min at 30°C. The reaction was stopped with 2% Na sulfite (40 ml / 2 ml) and the protease activity was determined using AAPF (see Example 2).

Tabelle 2: Verwendete Waschmittelmatrix

Figure imgf000117_0001
Table 2: Detergent matrix used
Figure imgf000117_0001

Verwendete Chemikalie: Natriumhypochlorit 14% CL in wässriger Lösung (GPR Rectapur, VWR #27900.296, CAS 7681-52-9); 14% Aktivchlor entspricht 140.000 ppm Chemical used: Sodium hypochlorite 14% CL in aqueous solution (GPR Rectapur, VWR #27900.296, CAS 7681-52-9); 14% active chlorine corresponds to 140,000 ppm

Es wurde eine 5.000 ppm Aktivchlorstocklösung in Waschmittelmatrix gemäß Tabelle 2 hergestellt und der pH-Wert mit 2M HCl auf pH 8 eingestellt. A 5,000 ppm active chlorine stock solution in detergent matrix was prepared according to Table 2 and the pH was adjusted to pH 8 with 2M HCl.

In eine Waschmittelmatrix gemäß Tabelle 2 wurden jeweils Proteasen gemäß Tabelle 1 in 0,5 ml gelöst eingearbeitet. Die proteasehaltigen Proben sowie Kontrollansätze (Waschmittel gemäß Tabelle 2, ohne Protease) wurden mit verschiedenen Konzentrationen Aktivchlor (0 ppm, 0,5 ppm, 1 ppm, 2 ppm, 4 ppm, 10 ppm) versetzt. Die Proben wurden 30 s gerührt und anschließend im Wasserbad für 30 min bei 30°C inkubiert. Nach der Inkubation wurden jeweils 2% Na-Sulfit (40 mg / 2ml) zur Inaktivierung des Aktivchlors hinzugegeben, die Proben wurden gemischt und bis zur Auswertung auf Eis gelagert. Proteases according to Table 1 were dissolved in 0.5 ml of a detergent matrix according to Table 2. The protease-containing samples and control samples (detergent according to Table 2, without protease) were treated with various concentrations of active chlorine (0 ppm, 0.5 ppm, 1 ppm, 2 ppm, 4 ppm, 10 ppm). The samples were stirred for 30 s and then incubated in a water bath for 30 min at 30°C. After incubation, 2% sodium sulfite (40 mg/2 ml) was added to inactivate the active chlorine. The samples were mixed and stored on ice until analysis.

In Tabelle 3 ist die Proteaseaktivität (bestimmt gemäß Beispiel 2) der jeweiligen Proteasen gezeigt. Die Aktivität der jeweiligen Protease nach Inkubation für 30 min bei 30°C ohne Zugabe von Aktivchlor wurde auf 100% normiert. The protease activity (determined according to Example 2) of the respective proteases is shown in Table 3. The activity of the respective protease after incubation for 30 min at 30°C without the addition of active chlorine was normalized to 100%.

Tabelle 3: Ergebnisse

Figure imgf000118_0001
Table 3: Results
Figure imgf000118_0001

Die erfindungsgemäßen Protease- Varianten (P2 bis P11) zeigen im Vergleich zum Wildtyp (P1) eine signifikant verbesserte Stabilität gegenüber Natriumhypochlorit. The protease variants according to the invention (P2 to P11) show significantly improved stability towards sodium hypochlorite compared to the wild type (P1).

Beispiel 4: Anwendung in Textilwaschmittel Example 4: Application in textile detergents

Mit der in Tabelle 2 genannten Matrix wurden weiterhin Waschversuche auf proteasesensitiven Anschmutzungen durchgeführt. Dabei wurde gefunden, dass erfindungsgemäße Proteasen (P2 bis P11) eine gegenüber dem Wildtyp (P1) verbesserte Reinigungsleistung aufweisen. Further washing tests were conducted on protease-sensitive soils using the matrix listed in Table 2. It was found that proteases according to the invention (P2 to P11) exhibit improved cleaning performance compared to the wild type (P1).

Beispiel 5: Anwendung in Maschinengeschirrspülmittel Example 5: Use in dishwasher detergent

Mit der in Tabelle 4 genannten Matrix wurden weiterhin maschinelle Geschirrspülversuche auf proteasesensitiven Anschmutzungen durchgeführt. Dabei wurde gefunden, dass erfindungsgemäße Proteasen (P2 bis P11) eine gegenüber dem Wildtyp (P1) verbesserte Reinigungsleistung aufweisen. Tabelle 4: Geschirrspülmaschinenmatrix

Figure imgf000119_0001
Further automatic dishwashing tests were conducted on protease-sensitive soils using the matrix listed in Table 4. It was found that proteases according to the invention (P2 to P11) exhibit improved cleaning performance compared to the wild type (P1). Table 4: Dishwasher matrix
Figure imgf000119_0001

Beispiel 6: Beispielformulierunqen Example 6: Sample formulations

Die erfindungsgemäßen Proteasen können in verschiedenen Wasch- und Reinigungsmittelzusammensetzungen eingesetzt werden und ihren Effekt verwirklichen. The proteases according to the invention can be used in various washing and cleaning compositions and realize their effect.

Tabelle 5: Flüssiqwaschmittel

Figure imgf000119_0002
Figure imgf000120_0001
Table 5: Liquid detergents
Figure imgf000119_0002
Figure imgf000120_0001

Tabelle 6: Feste Waschmittel

Figure imgf000120_0002
Table 6: Solid detergents
Figure imgf000120_0002

Tabelle 7: Zweiphasiqes Maschinenqeschirrspülmittel

Figure imgf000120_0003
Figure imgf000121_0001
Table 7: Two-phase dishwasher detergent
Figure imgf000120_0003
Figure imgf000121_0001

Claims

PATENTANSPRÜCHE PATENT CLAIMS 1 . Protease, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91%, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , 1. A protease which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L. 2. Protease nach Anspruch 1 , die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91%, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , 2. Protease according to claim 1, which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1 , (i) an mindestens zwei der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens zwei Aminosäuresubstitutionen, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt sind, und (i) at least two of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least two amino acid substitutions selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L. 3. Protease nach Anspruch 1 oder 2, die proteolytische Aktivität aufweist und eine Aminosäuresequenz umfasst, die zu der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge zu mindestens 70% und zunehmend bevorzugt zu mindestens 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91%, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5% oder 99% identisch ist, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer, vorzugsweise zwei der Positionen, die den Positionen 211 und 212 entsprechen, mindestens eine, vorzugsweise zwei Aminosäuresubstitution(en), die aus der aus M211 N, M211 L, P212D und P212H, vorzugsweise M211 L und/oder P212D, bestehenden Gruppe ausgewählt ist/sind, und 3. Protease according to claim 1 or 2, which has proteolytic activity and comprises an amino acid sequence which corresponds to the amino acid sequence given in SEQ ID NO:1 over its entire length to at least 70% and increasingly preferably to at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5% or 99% identical, wherein the protease, in each case based on the numbering according to SEQ ID NO:1 , (i) at least one, preferably two, of the positions corresponding to positions 211 and 212, at least one, preferably two amino acid substitution(s) selected from the group consisting of M211 N, M211 L, P212D and P212H, preferably M211 L and/or P212D, and (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L. 4. Protease nach einem der Ansprüche 1 bis 3, wobei die Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination aus Gruppe (i) aus der aus I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H und Q12L-M122L-A222S bestehenden Gruppe ausgewählt ist und die Aminosäuresubstitution bzw. Aminosäuresubstitutionskombination aus Gruppe (ii) aus der aus A29G, A29G-D58P, A29G-Y89A, A29G-M117A, A29G-M117F, A29G-M1171, A29G-M117L, A29G-M117V, A29G-M216A, A29G-M216F, A29G-M216L, A29G-D58P-Y89A, A29G-D58P-M117A, A29G-D58P-M117F, A29G-D58P-M1171, A29G-D58P-M117L, A29G-D58P-M117V, A29G-D58P- M216A, A29G-D58P-M216F, A29G-D58P-M216L, A29G-Y89A-M117A, A29G-Y89A-M117F, A29G- Y89A-M117I, A29G-Y89A-M117L, A29G-Y89A-M117V, A29G-Y89A-M216A, A29G-Y89A-M216F, A29G-Y89A-M216L, A29G-M117A-M216A, A29G-M117A-M216F, A29G-M117A-M216L, A29G-D58P- Y89A-M117A, A29G-D58P-Y89A-M117F, A29G-D58P-Y89A-M1171, A29G-D58P-Y89A-M117L, A29G-D58P-Y89A-M117V, A29G-D58P-Y89A-M216A, A29G-D58P-Y89A-M216F, A29G-D58P-Y89A- M216L, A29G-Y89A-M117A-M216A, A29G-Y89A-M117A-M216F, A29G-Y89A-M117A-M216L, A29G- Y89A-M117F-M216A, A29G-Y89A-M117F-M216F, A29G-Y89A-M117F-M216L, A29G-Y89A-M1171- M216A, A29G-Y89A-M117I-M216F, A29G-Y89A-M117I-M216L, A29G-Y89A-M117L-M216A, A29G- Y89A-M117L-M216F, A29G-Y89A-M117L-M216L, A29G-Y89A-M117V-M216A, A29G-Y89A-M117V- M216F, A29G-Y89A-M117V-M216L, D58P, D58P-Y89A, D58P-M117A, D58P-M117F, D58P-M1171, D58P-M117L, D58P-M117V, D58P-M216A, D58P-M216F, D58P-M216L, D58P-Y89A-M117A, D58P- Y89A-M117F, D58P-Y89A-M1171, D58P-Y89A-M117L, D58P-Y89A-M117V, D58P-Y89A-M216A, D58P-Y89A-M216F, D58P-Y89A-M216L, D58P-M117A-M216A, D58P-M117A-M216F, D58P-M117A- M216L, D58P-M117F-M216A, D58P-M117F-M216F, D58P-M117F-M216L, D58P-M117I-M216A, D58P-M117I-M216F, D58P-M117I-M216L, D58P-M117L-M216A, D58P-M117L-M216F, D58P-M117L- M216L, D58P-M117V-M216A, D58P-M117V-M216F, D58P-M117V-M216L, Y89A, Y89A-M117A, Y89A-M117F, Y89A-M1171, Y89A-M117L, Y89A-M117V, Y89A-M216A, Y89A-M216F, Y89A-M216L, Y89A-M117A-M216A, Y89A-M117A-M216F, Y89A-M117A-M216L, Y89A-M117F-M216A, Y89A- M117F-M216F, Y89A-M117F-M216L, Y89A-M117I-M216A, Y89A-M117I-M216F, Y89A-M1171- M216L, Y89A-M117L-M216A, Y89A-M117L-M216F, Y89A-M117L-M216L, Y89A-M117V-M216A, Y89A-M117V-M216F, Y89A-M117V-M216L, M117A, M117F, M117I, M117L, M117V, M117A-M216A, M117A-M216F, M117A-M216L, M117F-M216A, M117F-M216F, M117F-M216L, M117I-M216A, M117I-M216F, M117I-M216L, M117L-M216A, M117L-M216F, M117L-M216L, M117V-M216A, M117V-M216F, M117V-M216L, M216A, M216F, M216L, vorzugsweise M117A, M117A-Y89L, M117V, M117V-A29G, M117F, M117I, M117L, M216F, D58P-M216A, M216L, bestehenden Gruppe ausgewählt ist, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1. 4. Protease according to one of claims 1 to 3, wherein the amino acid substitution or amino acid substitution combination from group (i) is selected from the group consisting of I43V, M122L-N154S-T156A, M211 N-P212D, M211 L-P212D, G160S, D127P-M211 L-P212D, P212H and Q12L-M122L-A222S and the amino acid substitution or amino acid substitution combination from group (ii) is selected from the group consisting of A29G, A29G-D58P, A29G-Y89A, A29G-M117A, A29G-M117F, A29G-M1171, A29G-M117L, A29G-M117V, A29G-M216A, A29G-M216F, A29G-M216L, A29G-D58P-Y89A, A29G-D58P-M117A, A29G-D58P-M117F, A29G-D58P-M1171, A29G-D58P-M117L, A29G-D58P-M117V, A29G-D58P-M216A, A29G-D58P-M216F, A29G-D58P-M216L, A29G-Y89A-M117A, A29G-Y89A-M117F, A29G-Y89A-M117I, A29G-Y89A-M117L, A29G-Y89A-M117V, A29G-Y89A-M216A, A29G-Y89A-M216F, A29G-Y89A-M216L, A29G-M117A-M216A, A29G-M117A-M216F, A29G-M117A-M216L, A29G-D58P-Y89A-M117A, A29G-D58P-Y89A-M117F, A29G-D58P-Y89A-M1171, A29G-D58P-Y89A-M117L, A29G-D58P-Y89A-M117V, A29G-D58P-Y89A-M216A, A29G-D58P-Y89A-M216F, A29G-D58P-Y89A- M216L, A29G-Y89A-M117A-M216A, A29G-Y89A-M117A-M216F, A29G-Y89A-M117A-M216L, A29G- Y89A-M117F-M216A, A29G-Y89A-M117F-M216F, A29G-Y89A-M117F-M216L, A29G-Y89A-M1171-M216A, A29G-Y89A-M117I-M216F, A29G-Y89A-M117I-M216L, A29G-Y89A-M117L-M216A, A29G-Y89A-M117L-M216F, A29G-Y89A-M117L-M216L, A29G-Y89A-M117V-M216A, A29G-Y89A-M117V-M216F, A29G-Y89A-M117V-M216L, D58P, D58P-Y89A, D58P-M117A, D58P-M117F, D58P-M1171, D58P-M117L, D58P-M117V, D58P-M216A, D58P-M216F, D58P-M216L, D58P-Y89A-M117A, D58P-Y89A-M117F, D58P-Y89A-M1171, D58P-Y89A-M117L, D58P-Y89A-M117V, D58P-Y89A-M216A, D58P-Y89A-M216F, D58P-Y89A-M216L, D58P-M117A-M216A, D58P-M117A-M216F, D58P-M117A-M216L, D58P-M117F-M216A, D58P-M117F-M216F, D58P-M117F-M216L, D58P-M117I-M216A, D58P-M117I-M216F, D58P-M117I-M216L, D58P-M117L-M216A, D58P-M117L-M216F, D58P-M117L-M216L, D58P-M117V-M216A, D58P-M117V-M216F, D58P-M117V-M216L, Y89A, Y89A-M117A, Y89A-M117F, Y89A-M1171, Y89A-M117L, Y89A-M117V, Y89A-M216A, Y89A-M216F, Y89A-M216L, Y89A-M117A-M216A, Y89A-M117A-M216F, Y89A-M117A-M216L, Y89A-M117F-M216A, Y89A-M117F-M216F, Y89A-M117F-M216L, Y89A-M117I-M216A, Y89A-M117I-M216F, Y89A-M1171-M216L, Y89A-M117L-M216A, Y89A-M117L-M216F, Y89A-M117L-M216L, Y89A-M117V-M216A, Y89A-M117V-M216F, Y89A-M117V-M216L, M117A, M117F, M117I, M117L, M117V, M117A-M216A, M117A-M216F, M117A-M216L, M117F-M216A, M117F-M216F, M117F-M216L, M117I-M216A, M117I-M216F, M117I-M216L, M117L-M216A, M117L-M216F, M117L-M216L, M117V-M216A, M117V-M216F, M117V-M216L, M216A, M216F, M216L, preferably M117A, M117A-Y89L, M117V, M117V-A29G, M117F, M117I, M117L, M216F, D58P-M216A, M216L, each with reference to the numbering according to SEQ ID NO:1. 5. Protease, dadurch gekennzeichnet, dass 5. Protease, characterized in that (a) sie aus einer Protease nach einem der Ansprüche 1 bis 4 als Ausgangsmolekül erhältlich ist durch ein- oder mehrfache konservative Aminosäuresubstitution, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist; (a) it is obtainable from a protease according to any one of claims 1 to 4 as starting molecule by single or multiple conservative amino acid substitution, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L; (b) sie aus einer Protease nach einem der Ansprüche 1 bis 4 als Ausgangsmolekül erhältlich ist durch Fragmentierung, Deletions-, Insertions- oder Substitutionsmutagenese und eine Aminosäuresequenz umfasst, die über eine Länge von mindestens 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261 , 262, 263, 264, 265, 266, 267, 268 oder 269 zusammenhängenden Aminosäuren mit dem Ausgangsmolekül übereinstimmt, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. (b) it is obtainable from a protease according to any one of claims 1 to 4 as starting molecule by fragmentation, deletion, insertion or substitution mutagenesis and comprises an amino acid sequence which corresponds to the starting molecule over a length of at least 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268 or 269 contiguous amino acids, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L. 6. Verfahren zur Herstellung einer Protease, umfassend das Einbringen 6. A process for producing a protease, comprising introducing (i) mindestens einer Aminosäuresubstitution an mindestens einer der Positionen, die bezogen auf die Nummerierung gemäß SEQ ID NO:1 den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, ausgewählt aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe, und (i) at least one amino acid substitution at at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, based on the numbering according to SEQ ID NO:1, selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) mindestens einer Aminosäuresubstitution an mindestens einer der Positionen, die bezogen auf die Nummerierung gemäß SEQ ID NO:1 den Positionen 29, 58, 89, 117 und 216 entsprechen, ausgewählt aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe, in ein Ausgangsmolekül, das eine Aminosäuresequenz aufweist, die mindestens 70% und zunehmend bevorzugt zu mindestens 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90,5%, 91%, 91 ,5%, 92%, 92,5%, 93%, 93,5%, 94%, 94,5%, 95%, 95,5%, 96%, 96,5%, 97%, 97,5%, 98%, 98,5%, 99%, 99,5% oder 100% Sequenzidentität mit der in SEQ ID NO:1 angegebenen Aminosäuresequenz über deren Gesamtlänge aufweist. (ii) at least one amino acid substitution at at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, based on the numbering according to SEQ ID NO:1, selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L, in a starting molecule having an amino acid sequence which is at least 70% and increasingly preferably at least 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99%, 99.5% or 100% has sequence identity with the amino acid sequence given in SEQ ID NO:1 over its entire length. 7. Verfahren nach Anspruch 6, ferner umfassend einen oder mehreren der folgenden Verfahrensschritte: 7. The method according to claim 6, further comprising one or more of the following method steps: (a) Einbringen einer ein- oder mehrfachen konservativen Aminosäuresubstitution, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist; (a) introducing a single or multiple conservative amino acid substitution, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M1171, M117L, M117V, M216A, M216F and M216L; (b) Veränderung der Aminosäuresequenz durch Fragmentierung, Deletions-, Insertionsoder Substitutionsmutagenese derart, dass die Protease eine Aminosäuresequenz umfasst, die über eine Länge von mindestens 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261 ,262,263, 264, 265, 266, 267, 268 oder 269 zusammenhängenden Aminosäuren mit dem Ausgangsmolekül übereinstimmt, wobei die Protease, jeweils bezogen auf die Nummerierung gemäß SEQ ID NO:1 , (i) an mindestens einer der Positionen, die den Positionen 12, 43, 122, 127, 154, 156, 160, 211 , 212 und 222 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211 N, M211 L, P212D, P212H und A222S bestehenden Gruppe ausgewählt ist, und (ii) an mindestens einer der Positionen, die den Positionen 29, 58, 89, 117 und 216 entsprechen, mindestens eine Aminosäuresubstitution, die aus der aus A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F und M216L bestehenden Gruppe ausgewählt ist, aufweist. (b) altering the amino acid sequence by fragmentation, deletion, insertion or substitution mutagenesis such that the protease comprises an amino acid sequence which corresponds to the starting molecule over a length of at least 190, 200, 210, 220, 230, 240, 250, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268 or 269 contiguous amino acids, wherein the protease, in each case based on the numbering according to SEQ ID NO:1, (i) at least one of the positions corresponding to positions 12, 43, 122, 127, 154, 156, 160, 211, 212 and 222, at least one amino acid substitution selected from the group consisting of Q12L, I43V, M122L, D127P, N154S, T156A, G160S, M211N, M211L, P212D, P212H and A222S, and (ii) at least one of the positions corresponding to positions 29, 58, 89, 117 and 216, at least one amino acid substitution selected from the group consisting of A29G, D58P, Y89A, M117A, M117F, M117I, M117L, M117V, M216A, M216F and M216L. 8. Nukleinsäure codierend für eine Protease nach einem der Ansprüche 1 bis 5 oder codierend für eine nach einem Verfahren der Ansprüche 6 bis 7 erhaltene Protease. 8. Nucleic acid encoding a protease according to any one of claims 1 to 5 or encoding a protease obtained by a process of claims 6 to 7. 9. Vektor enthaltend eine Nukleinsäure nach Anspruch 8, insbesondere ein Klonierungsvektor oder ein Expressionsvektor. 9. Vector containing a nucleic acid according to claim 8, in particular a cloning vector or an expression vector. 10. Nicht-menschliche Wirtszelle, die eine Nukleinsäure nach Anspruch 8 oder einen Vektor nach Anspruch 9 beinhaltet, oder die eine Protease nach einem der Ansprüche 1 bis 5 beinhaltet, oder die eine nach einem Verfahren der Ansprüche 6 bis 7 erhaltene Protease beinhaltet, insbesondere eine, die die Protease in das die Wirtszelle umgebende Medium sezerniert. 10. A non-human host cell comprising a nucleic acid according to claim 8 or a vector according to claim 9, or comprising a protease according to any one of claims 1 to 5, or comprising a protease obtained by a process of claims 6 to 7, in particular one which secretes the protease into the medium surrounding the host cell. 11 . Verfahren zur Herstellung einer Protease umfassend a) Kultivieren einer Wirtszelle gemäß Anspruch 10 und b) Isolieren der Protease aus dem Kulturmedium oder aus der Wirtszelle. 11. A process for producing a protease comprising a) culturing a host cell according to claim 10 and b) isolating the protease from the culture medium or from the host cell. 12. Wasch- oder Reinigungsmittel, insbesondere bleichmittelhaltiges Wasch- oder Reinigungsmittel, bevorzugt Maschinengeschirrspülmittel, besonders bevorzugt bleichmittelhaltiges Maschinengeschirrspülmittel, dadurch gekennzeichnet, dass es mindestens eine Protease nach einem der Ansprüche 1 bis 5 oder eine nach einem Verfahren der Ansprüche 6 bis 7 erhaltene Protease enthält. 12. Washing or cleaning agent, in particular washing or cleaning agent containing bleach, preferably automatic dishwashing agent, particularly preferably automatic dishwashing agent containing bleach, characterized in that it contains at least one protease according to one of claims 1 to 5 or a protease obtained by a process according to claims 6 to 7. 13. Verfahren zur Reinigung von Textilien und/oder harten Oberflächen, insbesondere Geschirr, dadurch gekennzeichnet, dass in mindestens einem Verfahrensschritt ein Wasch- oder Reinigungsmittel nach Anspruch 12 angewendet wird. 13. A method for cleaning textiles and/or hard surfaces, in particular dishes, characterized in that a washing or cleaning agent according to claim 12 is used in at least one method step. 14. Verwendung einer Protease nach einem der Ansprüche 1 bis 5 oder eine nach einem Verfahren der Ansprüche 6 bis 7 erhaltene Protease in einem Wasch- oder Reinigungsmittel, insbesondere bleichmittelhaltiges Wasch- oder Reinigungsmittel, bevorzugt Maschinengeschirrspülmittel, besonders bevorzugt bleichmittelhaltiges Maschinengeschirrspülmittel, zur Reinigung von Textilien und/oder harten Oberflächen, insbesondere Geschirr. 14. Use of a protease according to any one of claims 1 to 5 or a protease obtained by a process according to claims 6 to 7 in a washing or cleaning agent, in particular a washing or cleaning agent containing bleach, preferably a dishwasher detergent, particularly preferably a dishwasher detergent containing bleach, for cleaning textiles and/or hard surfaces, in particular dishes.
PCT/EP2024/081351 2023-12-07 2024-11-06 Protease variants with improved bleach stability Pending WO2025119569A1 (en)

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