DE19957043A1 - New defensins - Google Patents
New defensinsInfo
- Publication number
- DE19957043A1 DE19957043A1 DE1999157043 DE19957043A DE19957043A1 DE 19957043 A1 DE19957043 A1 DE 19957043A1 DE 1999157043 DE1999157043 DE 1999157043 DE 19957043 A DE19957043 A DE 19957043A DE 19957043 A1 DE19957043 A1 DE 19957043A1
- Authority
- DE
- Germany
- Prior art keywords
- defensins
- defensin
- carboxyl group
- infections
- cys
- 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.)
- Withdrawn
Links
- 102000000541 Defensins Human genes 0.000 title abstract description 5
- 108010002069 Defensins Proteins 0.000 title abstract description 5
- 102000012265 beta-defensin Human genes 0.000 claims abstract description 26
- 108050002883 beta-defensin Proteins 0.000 claims abstract description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 4
- 150000001413 amino acids Chemical class 0.000 claims abstract description 3
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 2
- 241000588722 Escherichia Species 0.000 claims description 2
- 241000589516 Pseudomonas Species 0.000 claims description 2
- 241000191940 Staphylococcus Species 0.000 claims description 2
- 241000194017 Streptococcus Species 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical class [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 244000052769 pathogen Species 0.000 claims description 2
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000003115 biocidal effect Effects 0.000 abstract description 5
- 235000018417 cysteine Nutrition 0.000 abstract 2
- 235000001014 amino acid Nutrition 0.000 abstract 1
- 125000000539 amino acid group Chemical group 0.000 abstract 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 abstract 1
- 150000001945 cysteines Chemical group 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- NQLVQOSNDJXLKG-UHFFFAOYSA-N prosulfocarb Chemical compound CCCN(CCC)C(=O)SCC1=CC=CC=C1 NQLVQOSNDJXLKG-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4723—Cationic antimicrobial peptides, e.g. defensins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Gegenstand der vorliegenden Erfindung sind neue β-Defensine gemäß Anspruch 1, Arzneimittel enthaltend die erfindungsgemäßen β-Defensine sowie Verwendungen der erfindungsgemäßen β-Defensine.The present invention relates to new β-defensins according to Claim 1, medicament containing the β-defensins according to the invention and uses of the β-defensins according to the invention.
Defensine sind Polypeptide mit antibiotischer Wirkung. Aufgrund der zunehmenden Antibiotikaresistenz insbesondere von pathogenen Mikro organismen ist es dringend erforderlich, das Arsenal der antibiotisch wirksamen Substanzen zu ergänzen, um diese Mikroorganismen erfolg reich zu bekämpfen. Defensine werden in Säugern in verschiedenen Geweben und Organen exprimiert.Defensins are polypeptides with an antibiotic effect. Due to the increasing antibiotic resistance especially of pathogenic micro Organisms urgently need the arsenal of antibiotic effective substances to supplement to make these microorganisms successful fight rich. Defensins are found in various mammals Tissues and organs expressed.
Das der Erfindung zu Grunde liegende technische Problem bestand darin weitere wirksame Defensine zur Verfügung zu stellen, die unter ande rem als Arzneimittel eingesetzt werden können.The technical problem underlying the invention was to provide further effective defensins, which among others rem can be used as a drug.
Erfindungsgemäß gelöst wird das angesprochene technische Problem
durch
β-Defensine der Formel
According to the invention, the technical problem addressed is solved by
β-defensins of the formula
Z1-RCIGLXHKIGTC-Z2
Z 1 -RCIGLXHKIGTC-Z 2
wobei
X = F oder R ist und
Z1 gleich Z2 oder verschieden sind,
Z1 einen substituierten oder unsubstituierten Aminorest mit mindes
tens einem weiteren Cys bedeutet,
Z2 ein Peptidrest von bis zu 20 Aminosäuren ist und mindestens zwei
weitere unmittelbar benachbarte Cys oder eine Carboxylgruppe oder
eine derivatisierte Carboxylgruppe bedeutet.in which
X = F or R and
Z 1 are the same as Z 2 or are different,
Z 1 represents a substituted or unsubstituted amino radical with at least one further Cys,
Z 2 is a peptide residue of up to 20 amino acids and means at least two further immediately adjacent Cys or a carboxyl group or a derivatized carboxyl group.
In einer bevorzugten Ausführungsformen des erfindungsgemäßen β- Defensins bedeutet Z1 QDINSKRACYREGGECLQ und/oder QKINEPVSCIRNGGICQY und Z2 CNFRKCCKFQIPEKKTKIL und/oder GSPFKCCK.In a preferred embodiment of the β-defensin according to the invention, Z 1 means QDINSKRACYREGGECLQ and / or QKINEPVSCIRNGGICQY and Z 2 CNFRKCCKFQIPEKKTKIL and / or GSPFKCCK.
Fig. 1a zeigt einige Aminosäuresequenzen von bekannten humanen und murinen β-Defensinen. Die erfindungsgemäß besonders bevorzugten β- Defensine sind mBD5 (Seq ID. No 1) und mBD6 (Seq ID. No 2). Die anderen Sequenzen mBD1 bis mBD4 stammen aus der Maus und sind an sich bekannt, ebenso wie die Sequenzen hBD1 und hBD2. Letztere stammen aus dem Menschen. Figure 1a shows some amino acid sequences from known human and murine β-defensins. The β-defensins which are particularly preferred according to the invention are mBD5 (Seq ID. No 1) and mBD6 (Seq ID. No 2). The other sequences mBD1 to mBD4 originate from the mouse and are known per se, as are the sequences hBD1 and hBD2. The latter come from humans.
Fig. 1b zeigt die erfindungsgemäßen β-Defensine mBD5 (Seq ID. No 1) und mBD6 (Seq ID. No 2). FIG. 1b shows the inventive β-defensins mBD5 (Seq ID. No 1) and mBD6 (Seq ID. No 2).
Fig. 2 zeigt ein Expressionsmuster des erfindungsgemäßen β-Defensins mBD5 in verschiedenen Geweben oder Organen der Maus. Die Ordinate ist in relativen Expressionseinheiten angegeben. Fig. 2 shows a pattern of expression of the inventive β-defensin mBD5 in various tissues or organs of the mouse. The ordinate is given in relative expression units.
Fig. 3 zeigt ein Expressionmuster des erfindungsgemäßen β-Defensins mBD6 in verschiedenen Geweben oder Organen der Maus: Die Ordinate ist in relativen Expressionseinheiten angegeben. Fig. 3 shows the inventive β-defensin mBD6 in different tissues or organs of the mouse, an expression pattern: The ordinate is indicated in relative expression units.
Fig. 4 zeigt in Tabellenform die minimale Hemmkonzentration (MIC mi nimum inhibitory concentration) der erfindungsgemäßen β-Defensine gegenüber verschiedenen Mikroorganismen. Die Werte sind in µg/mL angegeben. Fig. 4, the minimum inhibitory concentration (MIC mi nimum inhibitory concentration) are presented in tabular form of the β-defensins of the invention against various microorganisms. The values are given in µg / mL.
Fig. 5 zeigt eine Dosis-Wirkungskurve der erfindungsgemäßen β- Defensine. Die Ordinate der oberen Kurve zeigt als Angabe den cfu-Wert (colony forming units), die Abszisse die steigende Konzentration des β- Defensins mBD5 sowie die daraus abgeleitete Ermittlung des IC50 Wert (inhibitory concentration) für mBD5 gegen E. coli. Die untere Kurve zeigt dies entsprechend für mBD6. Fig. 5 is a dose response curve showing the β- defensins of the invention. The ordinate of the upper curve shows the cfu value (colony forming units), the abscissa the increasing concentration of the β-defensin mBD5 and the derived determination of the IC 50 value (inhibitory concentration) for mBD5 against E. coli. The lower curve shows this accordingly for mBD6.
Fig. 6 zeigt die Regulierung des erfindungsgemäßen β-Defensins mBD5 in NIH-3T3 Zellen. Die Ordinate zeigt relative Expressionseinheiten. Fig. 6 shows the regulation of the inventive β-defensin mBD5 in NIH-3T3 cells. The ordinate shows relative expression units.
Die erfindungsgemäßen Arzneimittel enthalten als wirksamen Bestand teil mindestens ein erfindungsgemäßes β-Defensin. Dem Fachmann sind die gegebenenfalls zur Formulierung der β-Defensine als Arzneimittel einsetzbaren Hilfs- und Trägerstoffe geläufig. Die β-Defensine können in Mengen eingesetzt werden, die durch ihre therapeutische Breite defi niert sind. Typischerweise werden sie in Mengen von 1 µg bis 100 mg eingesetzt.The medicaments according to the invention contain as an effective stock partly at least one β-defensin according to the invention. The specialist are which may be used to formulate the β-defensins as drugs usable auxiliaries and carriers. The β-defensins can be found in Amounts are used that defi due to their therapeutic range are nated. They are typically used in amounts of 1 µg to 100 mg used.
Die Formulierungen der erfindungsgemäßen β-Defensine als Lösung für intravenöse, intramusculare, subkutane und topische Applikation sind bevorzugt.The formulations of the β-defensins according to the invention as a solution for intravenous, intramuscular, subcutaneous and topical application prefers.
Die erfindungsgemäßen β-Defensine sind zur Behandlung von Infektio nen geeignet. Insbesondere können die erfindungsgemäßen als antibio tisch wirksame Substanz eingesetzt werden. Das antibiotische Spektrum der erfindungsgemäßen β-Defensirie ist weit und reicht zum Beispiel zur Behandlung von Infektionen durch multiresistente Erreger, wie Strepto kokkus, Bacillus, Pseudomonas, Escherichia, Staphylokokkus und Candi da.The β-defensins according to the invention are for the treatment of infection suitable. In particular, the antibiotics according to the invention table active substance can be used. The antibiotic spectrum the β-defensie according to the invention is wide and, for example, sufficient for Treatment of infections caused by multi-resistant pathogens, such as strepto coccus, Bacillus, Pseudomonas, Escherichia, Staphylococcus and Candi there.
Claims (6)
Z1-RCIGLXHKIGTC-Z2
wobei
X = F oder R ist und
Z1 gleich Z2 oder verschieden sind,
Z1 einen substituierten oder unsubstituierten Aminorest mit mindes tens einem weiteren Cys bedeutet,
Z2 ein Peptidrest von bis zu 20 Aminosäuren ist, und mindestens zwei weitere unmittelbar benachbarte Cys oder eine Carboxylgruppe oder derivatisierte Carboxylgruppe bedeutet.1. β-defensins of the formula
Z 1 -RCIGLXHKIGTC-Z 2
in which
X = F or R and
Z 1 are the same as Z 2 or are different,
Z 1 represents a substituted or unsubstituted amino radical with at least one further Cys,
Z 2 is a peptide residue of up to 20 amino acids, and means at least two further immediately adjacent Cys or a carboxyl group or derivatized carboxyl group.
Z1 = QDINSKRACYREGGECLQ und/oder QKINEPVSCIRNGGICQY und
Z2 = CNFRKCCKFQIPEKKTKIL und/oder GSPFKCCK ist.2. β-defensin according to claim 1, wherein
Z 1 = QDINSKRACYREGGECLQ and / or QKINEPVSCIRNGGICQY and
Z 2 = CNFRKCCKFQIPEKKTKIL and / or GSPFKCCK.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1999157043 DE19957043A1 (en) | 1999-11-26 | 1999-11-26 | New defensins |
| AU23593/01A AU2359301A (en) | 1999-11-26 | 2000-11-25 | Novel ss-defensins |
| PCT/EP2000/011770 WO2001038349A2 (en) | 1999-11-26 | 2000-11-25 | NOVEL ss-DEFENSINS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1999157043 DE19957043A1 (en) | 1999-11-26 | 1999-11-26 | New defensins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19957043A1 true DE19957043A1 (en) | 2001-06-07 |
Family
ID=7930487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1999157043 Withdrawn DE19957043A1 (en) | 1999-11-26 | 1999-11-26 | New defensins |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU2359301A (en) |
| DE (1) | DE19957043A1 (en) |
| WO (1) | WO2001038349A2 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2002327026A1 (en) * | 2001-09-21 | 2003-04-01 | University Of Iowa Research Foundation | Human and mouse beta-defensins, antimicrobial peptides |
| WO2004055041A2 (en) * | 2002-12-13 | 2004-07-01 | Case Western Reserve University | Defensin-inducing peptides from fusobacterium |
| US7442375B2 (en) | 2002-12-13 | 2008-10-28 | Case Western Reserve University | Compositions of beta-defensin inducing agents |
| AU2003301012A1 (en) * | 2002-12-13 | 2004-07-09 | Case Western Reserve University | Use of beta-defensins for treating hiv infections |
| DE102005014687A1 (en) * | 2005-03-29 | 2006-10-12 | Henkel Kgaa | Composition containing β-defensin 2 |
| MX2011000568A (en) | 2008-07-18 | 2011-02-23 | Novozymes Adenium Biotech As | Treatment of inflammatory bowel diseases with mammal beta defensins. |
| US9217021B2 (en) | 2011-07-08 | 2015-12-22 | Defensin Therapeutics Aps | Oral treatment of inflammatory bowel disease |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1012285B1 (en) * | 1997-09-10 | 2005-08-03 | ZymoGenetics, Inc. | Beta-defensins |
-
1999
- 1999-11-26 DE DE1999157043 patent/DE19957043A1/en not_active Withdrawn
-
2000
- 2000-11-25 WO PCT/EP2000/011770 patent/WO2001038349A2/en not_active Ceased
- 2000-11-25 AU AU23593/01A patent/AU2359301A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001038349A2 (en) | 2001-05-31 |
| WO2001038349A3 (en) | 2002-05-10 |
| AU2359301A (en) | 2001-06-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8139 | Disposal/non-payment of the annual fee |