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WO2003018609A2 - Application de conjugues peptides a la maladie d'alzheimer - Google Patents

Application de conjugues peptides a la maladie d'alzheimer Download PDF

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Publication number
WO2003018609A2
WO2003018609A2 PCT/US2002/026889 US0226889W WO03018609A2 WO 2003018609 A2 WO2003018609 A2 WO 2003018609A2 US 0226889 W US0226889 W US 0226889W WO 03018609 A2 WO03018609 A2 WO 03018609A2
Authority
WO
WIPO (PCT)
Prior art keywords
peptide
chemical compound
disease
alzheimer
phenylalanine
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.)
Ceased
Application number
PCT/US2002/026889
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English (en)
Other versions
WO2003018609A3 (fr
Inventor
Stanley Stein
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.)
Individual
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to AU2002327514A priority Critical patent/AU2002327514A1/en
Publication of WO2003018609A2 publication Critical patent/WO2003018609A2/fr
Publication of WO2003018609A3 publication Critical patent/WO2003018609A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • Tjernberg et al (Tjernberg et al , 1996) first synthesized the 31 possible 10-mers corresponding to ammo acids 1-10 up to 31-40 of the A ⁇ ' "40 molecule on a cellulose memberane matrix
  • the A ⁇ fragments capable of binding full length A ⁇ were identified by radio gand binding A region located in the central part of A ⁇ ( A ⁇ 1S to A ⁇ 13 22 ) displayed prominent binding to A ⁇ Being located in the center of the binding region, A ⁇ " 20 was selected for further studies of the structural requirements for binding This peptide, as well as N- and C-terminally truncated fragments, were synthesized and tested It was found that the shortest peptide still displaying consistent high A ⁇ binding capacity had the sequence KLVFF(correspond ⁇ ng to A ⁇ 1620 ) This result agreed with Hilbich et al This peptide was studied by microscopy and was found to be able to inhibit fibril formation in vitro
  • Shao et al (Shao et al., 1999) determined the structure of ⁇ -amyloid peptide by NMR in sodium dodecyl sulfate (SDS) solution. Since SDS is a strong denaturating reagent, this structural information may not be applicable to the native peptide. [036] Another way to study the structure of this peptide is by molecular modeling. From the primary structure of ⁇ amyloid peptide, there are two hydrophobic regions: Leul7-Ala21 and residue 28 to the end of the C-terminus. The first hydrophobic core has an alpha-helix structure stabilized by intramolecular hydrogen bonding.
  • Amyloid fibrils are composed of five or six protofilaments arranged around a hollow center, each protofilament having a diameter of around 25-30 A (Serpell 2000b).
  • the full sequence listing of ⁇ -amyloid peptide is shown in Figure 3. [038] Designing peptides
  • this peptide carrier Comparing to the PEG-aspartic acid copolymer, this peptide carrier has the shortest spacer between the primary amine functional group, which is used to attach the peptide. We will put the peptide on these peptide carriers and evaluate them. We will compare these conjugates with the single peptide and also compare these conjugates with each other to study the effect of spacer length. [046] In the description and Examples that follow conjugates according to the invention will be synthesized and evaluated.
  • This conjugates was made by coupling HOOC-PEG 600 -(N-Fmoc)-KLVFF with PEG-aspartic acid copolymer This reaction was done in solution phase Because PEG has the property of absorbing water readily in the air, both materials are dried in the vacuum overnight PEG-aspartic acid copolymer (80 mg,
  • the peptide ( ⁇ -Boc)-K-( ⁇ -Boc)-KLVFF was synthesized by the standard solid phase synthesis using the Fmoc chemistry described before. With the peptide still on the resin and the Fmoc on the N- terminus removed, 10 equivalent of PEG 600 -(COOH) 2 was dissolved in DMF containing 2% DIEA and added to the polypropylene column containing the resin. Then 5 equivalents of BOP and Hobt were added as coupling reagents. The coupling reaction was done at room temperature for 2 hours with constant shaking. The resin was then washed with DMF, methanol and then DCM, just like the procedure in peptide synthesis.
  • peptide drug One important drawback of peptide drug is its instability in vivo. There are a lot of protease in the body that can digest the peptide before the drug can be absorbed and perform its pharmacological effect. Therefore, we tried to make the peptide protease resistant by using all D-amino acids, which are non- natural.
  • the peptide KLVFF with free carboxylic acid C-terminal was purchased from Bachem.
  • the ThT assay for this peptide was done and compared with that with amide C-terminal to study the charge effect in the C-terminal.
  • the inhibitory effect of KLVFF with amide C-terminal is significantly better than that with free acid C-terminal.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Food Science & Technology (AREA)
  • Neurosurgery (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Neurology (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Microbiology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un composé chimique et son procédé d'utilisation dans le diagnostic et le traitement de la maladie d'Alzheimer. Au moins la séquence des isomères-D des acides aminés (phénylalanine-phénylalanine-valine-leucine-lysine) est en mesure de traverser la barrière sang-cerveau, de reconnaître la formation de plaques, caractéristique de la pathogénie de la maladie d'Alzheimer, et de perturber la formation d'une fibrille du peptide amyloïde beta par inhibition du processus de la maladie.
PCT/US2002/026889 2001-08-23 2002-08-23 Application de conjugues peptides a la maladie d'alzheimer Ceased WO2003018609A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002327514A AU2002327514A1 (en) 2001-08-23 2002-08-23 Application of peptide conjugates to alzheimer's disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US31438201P 2001-08-23 2001-08-23
US60/314,382 2001-08-23

Publications (2)

Publication Number Publication Date
WO2003018609A2 true WO2003018609A2 (fr) 2003-03-06
WO2003018609A3 WO2003018609A3 (fr) 2003-10-16

Family

ID=23219731

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/026889 Ceased WO2003018609A2 (fr) 2001-08-23 2002-08-23 Application de conjugues peptides a la maladie d'alzheimer

Country Status (2)

Country Link
AU (1) AU2002327514A1 (fr)
WO (1) WO2003018609A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007129077A3 (fr) * 2006-05-05 2008-01-03 St Georges Hosp Medical School Agent d'imagerie
WO2008050133A3 (fr) * 2006-10-27 2008-06-19 Zyentia Ltd Inhibition d'une agrégation de beta-amyloïde
JP2010537962A (ja) * 2007-08-30 2010-12-09 ユナイティッド アラブ エミレーツ ユニヴァーシティ 診断薬剤
WO2013054110A3 (fr) * 2011-10-10 2013-05-30 Lancaster University Business Enterprises Limited Compositions de liaison aux protéines amyloïdes
CN113061161A (zh) * 2021-04-02 2021-07-02 河南省农业科学院动物免疫学重点实验室 靶向amyloid-beta结构的抑制性肽配基及应用
CN114933635A (zh) * 2021-08-29 2022-08-23 华中科技大学同济医学院附属协和医院 纳米小肽fh及其在制备治疗及预防眼底血管疾病药物中的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020094335A1 (en) * 1999-11-29 2002-07-18 Robert Chalifour Vaccine for the prevention and treatment of alzheimer's and amyloid related diseases

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007129077A3 (fr) * 2006-05-05 2008-01-03 St Georges Hosp Medical School Agent d'imagerie
WO2008050133A3 (fr) * 2006-10-27 2008-06-19 Zyentia Ltd Inhibition d'une agrégation de beta-amyloïde
JP2010537962A (ja) * 2007-08-30 2010-12-09 ユナイティッド アラブ エミレーツ ユニヴァーシティ 診断薬剤
WO2013054110A3 (fr) * 2011-10-10 2013-05-30 Lancaster University Business Enterprises Limited Compositions de liaison aux protéines amyloïdes
US9579358B2 (en) 2011-10-10 2017-02-28 Lancaster University Business Enterprises Limited Compositions for binding to amyloid proteins
CN113061161A (zh) * 2021-04-02 2021-07-02 河南省农业科学院动物免疫学重点实验室 靶向amyloid-beta结构的抑制性肽配基及应用
CN113061161B (zh) * 2021-04-02 2023-09-12 河南省农业科学院动物免疫学重点实验室 靶向amyloid-beta结构的抑制性肽配基及应用
CN114933635A (zh) * 2021-08-29 2022-08-23 华中科技大学同济医学院附属协和医院 纳米小肽fh及其在制备治疗及预防眼底血管疾病药物中的应用

Also Published As

Publication number Publication date
AU2002327514A1 (en) 2003-03-10
WO2003018609A3 (fr) 2003-10-16

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