EP0546101A1 - PROCEDE PERMETTANT D'INTERFERER AVEC LA FORMATION DU COMPLEXE $g(a)-ANTICHYMOTRYPSINE/$g(b)-PROTEINE, ET PEPTIDES SYNTHETIQUES UTILISES DANS CE PROCEDE - Google Patents

PROCEDE PERMETTANT D'INTERFERER AVEC LA FORMATION DU COMPLEXE $g(a)-ANTICHYMOTRYPSINE/$g(b)-PROTEINE, ET PEPTIDES SYNTHETIQUES UTILISES DANS CE PROCEDE

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Publication number
EP0546101A1
EP0546101A1 EP91917880A EP91917880A EP0546101A1 EP 0546101 A1 EP0546101 A1 EP 0546101A1 EP 91917880 A EP91917880 A EP 91917880A EP 91917880 A EP91917880 A EP 91917880A EP 0546101 A1 EP0546101 A1 EP 0546101A1
Authority
EP
European Patent Office
Prior art keywords
protein
act
alzheimer
antichymotrypsin
complex
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Withdrawn
Application number
EP91917880A
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German (de)
English (en)
Inventor
Huntington Potter
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.)
Harvard University
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Harvard University
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Filing date
Publication date
Application filed by Harvard University filed Critical Harvard University
Publication of EP0546101A1 publication Critical patent/EP0546101A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8121—Serpins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/44—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving esterase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/81—Protease inhibitors
    • G01N2333/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • G01N2333/811—Serine protease (E.C. 3.4.21) inhibitors
    • G01N2333/8121—Serpins
    • G01N2333/8125—Alpha-1-antitrypsin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/20—Screening for compounds of potential therapeutic value cell-free systems
    • 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

  • Alzheimer's disease is a degenerative disorder of the central nervous system that results in a progressive loss of memory and other intellectual functions, such as reasoning, orientation, and judgement (R. Katzman, Banbury Report 15: Biological Aspects of Alzheimer's Disease, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, (1983)).
  • Alzheimer's disease occurs in sporadic and familial forms, and in the United States, affects about 600 people for every 100,000.
  • a characteristic aspect of the neuropathology of the disease is the
  • amyloid proteinaceous deposits referred to as "amyloid" in the cores of brain lesions called neuritic or senile plaques, as well as in cerebral blood vessels.
  • the "amyloid” deposits are generally defined as 6-10 nm protein filaments with certain staining properties (Abraham, C.R. et al., Cell,
  • Amyloid deposits are also found in the brains of aged humans, although not as extensively as in Alzheimer's disease. Further, Down's syndrome patients more than 30 or 40 years old invariably develop the symptoms and neuropathology characteristic of Alzheimer's disease.
  • One component of the amyloid deposits was identified as A4 amyloid or y9-protein ( ⁇ -protein) and is 42 amino ac ids long ( G l enner , G . G and C . G . Wong , Biochem. Biophys. Res. Commun. 120 : 885 - 890 (1984)). This protein is apparently derived from a larger membrane-spanning precursor protein which is alternately spliced to yield several products
  • Alzheimer's disease As mentioned above, some cases of Alzheimer's disease appear to be familial, and are inherited in an autosomal dominant fashion. Linkage analysis in four families pointed to a lesion on the long arm of chromosome 21 (St. George-Hyslop, P.H. et al.,
  • hereditary cerebral hemorrhage with amyloidosis of Dutch origin was reported to be linked to the APP gene, and a point mutation in the coding region of the gene was identified (Van Broeckhoven, C. et al.. Science, 248:1120-1122 (1990); Levy, E. et al., Science, 248 :1124-1126 (1990)). Patients with this disease have a form of the ⁇ -protein in amyloid deposits in meningeal and cerebral blood vessels.
  • APP amyloid precursor protein
  • ⁇ 1 -antichymotryps in (ACT) ⁇ 1 -antichymotryps in (ACT)
  • This invention relates to a novel class of synthetic peptides or peptide-like compounds which mimic a component of a specific complex between the Alzheimer's ⁇ -protein and ACT, and which are useful to interfere with formation of the complex.
  • the invention also relates to a method of treating an individual in whom such complexes form, resulting directly or indirectly in an abnormal condition or disease state, and particularly to a method of treating an individual with Alzheimer's disease.
  • the synthetic peptides of the present invention which inhibit complex formation between the Alzheimer's ⁇ -protein and ACT by binding to the ⁇ -protein or to ACT, can be administered to an individual in such a manner as to interfere with the ACT- ⁇ -protein interaction, and in sufficient quantity so as to have the desired effect (i.e., reduction of complex formation and the abnormal disease state).
  • Figure 1 is the amino acid sequence of
  • Alzheimer amyloid ⁇ -protein (top row) and the active sites of the following five serine proteases:
  • cytotoxic T cell protease cytotoxic T cell protease
  • cathepsin G mast cell protease
  • trypsin trypsin
  • chymotrypsin cytotoxic T cell protease
  • Figure 2 is a graphic representation of the protease regulatory activity of Alzheimer amyloid ⁇ -protein. De tai l e d Descri p t ion o f the I nvent io n
  • protease inhibitor ⁇ 1 -antichymotrypsin (ACT) and the 42-aa ⁇ -protein are integral components of the brain amyloid deposits of Alzheimer's disease, Down's syndrome, and normal aging. This indicates that there is a special affinity between ACT and the ⁇ -protein, perhaps essential to amyloid formation. A basis for this association is suggested by the similarity of the N-terminus of ⁇ -protein to the active site of serine proteases.
  • Such synthetic peptides include peptides and peptide-like compounds (e.g., modified or derivatized peptides) which interfere with interaction of ACT with ⁇ -protein, particularly peptides which "mimic" the active (or binding) site of serine proteases.
  • Such peptides can be short peptides in which the amino acid sequence is sufficiently homologous with the sequence of the binding site of a serine protease or with the N-terminus of ⁇ - protein as shown in Figure 1, that they bind with ACT.
  • such peptides can include, in addition to the sequence sufficiently homologous with the serine protease binding site or ⁇ -protein region, other amino acids (e.g., one or more amino acids at either or both ends of the binding site sequence).
  • a compound of the present invention is introduced into an individual in such a manner that it interferes with formation of the ACT- ⁇ -prote in complex.
  • a compound is administered in sufficient quantity and by an appropriate route to have a therapeutic effect. The following is a description of the
  • the present invention can be used in the treatment of individuals, such as those with
  • extracellular amyloid filaments found in the plaques and blood vessels of Alzheimer's disease, Down's syndrome, and normal aging contain two proteins, both intimately associated with the filaments - the 42 amino acid ⁇ -protein and the serine protease inhibitor, ⁇ 1 -antichymotrypsin
  • HCVWA-D the major component of the vascular amyloid in the Dutch variant of hereditary cerebral hemorrhage with amyloidos
  • HHWA-I the ⁇ -protein, not cystatin C, as in the Icelandic version
  • HHWA-I the angiopathy appears similar
  • ACT is a serine protease inhibitor that functions by acting as a pseudosubs tr ate and binding covalently to its target protease to form a long-lived complex (J. Travis, et al., Biochemistry, 17:5651 (1978)).
  • Figure 2 shows the results of assessment of protease activity, carried out with the synthetic peptides.
  • the ACT/chymotrypsin molar ratio was approximately 1:1
  • the ACT inhibited over 90 percent of the chymotrypsin activity.
  • the inhibitory activity of ACT was substantially reduced and the chymotrypsin reaction rate increased 2 to 8-fold.
  • protease inhibitors Unlike true substrates that form a transient covalent intermediate with the protease through the hydroxyl group of its reactive serine, and then become cleaved as the bond breaks and the protease resumes its active state, protease inhibitors become cleaved, but only very slowly release their attachment to the protease (J . Travis, e t a l . , Biochemistry, 17:5651 (1978)). Thus, the inhibitors essentially inactivate the protease in a suicidal, stoichiometric interaction.
  • serine protease inhibitors form stable complexes with their target proteases and that a serine protease inhibitor, ACT, is an integral component of the insoluble Alzheimer amyloid deposits, suggests that this protein might be incorporated into the filaments through a stable inhibitor-protease interaction.
  • ACT- - ⁇ -protein interaction occurs at the protease inhibitory site of ACT was confirmed by the fact that the addition of chymotrypsin to ACT prior to the radioactive peptide prevented the formation of the ACT-peptide complex. Heat denaturation of ACT prior to the addition of the peptide also prevented complex formation.
  • the work described indicates that the two components of the Alzheimer amyloid deposits ⁇ - -ACT and the ⁇ -protein- - can associate in vitro to form an SDS-stable complex.
  • the interaction is specific for both the peptide and the ACT protein, and likely occurs between the active protease inhibitor site of ACT and the N-terminus of the ⁇ -protein, which resembles the active site of serine proteases.
  • ACT serine protease inhibitor
  • ACT- ⁇ -protein complexes As a result of the discovery of the specific interaction between ACT and Alzheimer ⁇ -protein, it is possible to design or select compounds which are useful to interfere with (reduce or prevent) this ACT- ⁇ -protein interaction. The discovery has also made possible a method of preventing the interaction.
  • the compounds and method are particularly useful in reducing formation of ACT- ⁇ - protein complexes in individuals in whom such complexes form and result, directly or indirectly, in an abnormal or undesirable condition or a disease state. For example, such compounds can be used to reduce (totally or partially) or prevent formation of ACT- ⁇ -protein complexes in individuals who have Alzheimer's disease or would, without appropriate treatment, develop Alzheimer's disease.
  • Compounds of the present invention can be used, to interfere with binding of ACT and Alzheimer's ⁇ -protein, either by binding to ACT, thus preventing formation of the ACT- ⁇ -protein complex, or by bind- ing to ⁇ -protein, also preventing formation of the ACT- ⁇ protein complex.
  • a peptide corresponding to all or a portion of the amino acid sequence of a serine protease, such as all or a por- tion of the sequence of the Alzheimer's ⁇ -protein can be used.
  • a synthetic peptide which mimics the amino acid sequence of the inhibitory active site of ACT can be used to interfere with ACT- ⁇ -protein complex formation.
  • This type of peptide will bind to the ⁇ -protein, resulting in the production of a synthetic peptide- ⁇ -protein complex and, in essence, will "tie up" ⁇ -protein, precluding the ⁇ -protein from interacting with ACT.
  • ACT is a serine protease inhibitor and Alzheimer's ⁇ -protein has been shown to inhibit ACT's ability to inhibit a serine protease (i.e., chymotrypsin).
  • a serine protease i.e., chymotrypsin.
  • ⁇ -protein although not itself a protease, enhances protease activity by effectively increasing proteolytic activity (i.e., by reducing ACT's ability to exhibit serine proteases).
  • the discovery described herein also makes it possible to identify ACT- ⁇ -protein complexes in tissue obtained from an individual, such as in biopsy tissues obtained from an individual suspected of having abnormally high levels of the complexes. This can be used, for example, to determine the presence or absence and, if desired, the quantity of ACT- ⁇ -protein complexes in brain tissue obtained at autopsy.
  • a synthetic peptide of the present invention can be administered in a physiologically acceptable carrier (e.g., an appropriate buffer or physiologic saline solution). It can be administered by any route via which it is possible to deliver a physiologically acceptable carrier.
  • a physiologically acceptable carrier e.g., an appropriate buffer or physiologic saline solution. It can be administered by any route via which it is possible to deliver a physiologically acceptable carrier.
  • a synthetic peptide of the present invention is a synthetic peptide of the present invention.
  • inventions can be administered parenterally (e.g., intravenously or intramuscularly) in a composition which protects the peptide from degradation.
  • a synthetic peptide of the present invention can be made using known techniques, such as
  • ACT concentration of ACT. If a four-fold molar excess of either of the two synthetic peptides from the N-terminal portion of the ⁇ -protein (corresponding to amino acids 1-28 and 1-12 respectively) are added to ACT prior to the protease assay, they interfere with the inhibitory activity of ACT. In contrast, the control peptide corresponding to amino acids 258-277 of the ⁇ -protein precursor does not modulate ACT's ability to inhibit chymotrypsin.

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Abstract

Procédé permettant d'interférer avec la formation d'un complexe dalpha1-antichymotrypsine et de beta-protéine d'Alzheimer, et peptides synthétiques utiles dans ce procédé. Le procédé et les peptides sont utiles pour la prévention de la formation de tels complexes chez des individus.
EP91917880A 1990-08-24 1991-08-22 PROCEDE PERMETTANT D'INTERFERER AVEC LA FORMATION DU COMPLEXE $g(a)-ANTICHYMOTRYPSINE/$g(b)-PROTEINE, ET PEPTIDES SYNTHETIQUES UTILISES DANS CE PROCEDE Withdrawn EP0546101A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US57267190A 1990-08-24 1990-08-24
US572671 1990-08-24

Publications (1)

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EP0546101A1 true EP0546101A1 (fr) 1993-06-16

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EP91917880A Withdrawn EP0546101A1 (fr) 1990-08-24 1991-08-22 PROCEDE PERMETTANT D'INTERFERER AVEC LA FORMATION DU COMPLEXE $g(a)-ANTICHYMOTRYPSINE/$g(b)-PROTEINE, ET PEPTIDES SYNTHETIQUES UTILISES DANS CE PROCEDE

Country Status (3)

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EP (1) EP0546101A1 (fr)
JP (1) JPH06500560A (fr)
WO (1) WO1992003474A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022198266A1 (fr) * 2021-03-22 2022-09-29 Ip Reserve Pty Ltd Ensemble rampe de mise à niveau

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5338663A (en) * 1990-08-24 1994-08-16 President And Fellows Of Harvard College Method of identifying inhibitors of β-protein esterase activity
US5506097A (en) * 1990-08-24 1996-04-09 President And Fellows Of Harvard College Method for inhibiting β-protein enzymatic activity
US5780587A (en) * 1990-08-24 1998-07-14 President And Fellows Of Harvard College Compounds and methods for inhibiting β-protein filament formation and neurotoxicity
WO1994009364A1 (fr) * 1992-10-13 1994-04-28 Duke University Procede permettant d'inhiber la liaison de la proteine precurseur d'amyloide a la proteine beta-amyloide
CA2125467C (fr) * 1993-07-06 2001-02-06 Heinz Dobeli Methode de preparation de polypeptides, proteines ou peptides hydrophobes
ES2173130T3 (es) 1993-10-20 2002-10-16 Univ Duke Metodo de fijacion de material al peptido beta-amiloide.
US6472140B1 (en) * 1997-09-05 2002-10-29 The General Hospital Corporation α-2- macroglobulin therapies and drug screening methods for Alzheimer's disease.
US6342350B1 (en) 1997-09-05 2002-01-29 The General Hospital Corporation Alpha-2-macroglobulin diagnostic test
AU2002254999B2 (en) * 2001-04-30 2007-07-26 Bayer Innovation Gmbh Use of alpha 1-antichymotrypsin for the manufacture of a composition for treatment, prevention or diagnosis of poorly healing diabetic or arterial wounds
CA2487528A1 (fr) * 2002-07-24 2004-02-12 Innogenetics N.V. Prevention, traitement et diagnostic de maladies associees a la formation et/ou a l'agregation de la beta-amyloide
GB0821624D0 (en) * 2008-11-26 2008-12-31 Eisai London Res Lab Ltd Assay
EP3802568A4 (fr) * 2018-06-08 2022-07-13 The Board of Regents of the University of Oklahoma Agents thérapeutiques peptidiques pour le traitement de la maladie d'alzheimer et d'états apparentés

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9203474A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022198266A1 (fr) * 2021-03-22 2022-09-29 Ip Reserve Pty Ltd Ensemble rampe de mise à niveau

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WO1992003474A1 (fr) 1992-03-05

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