CA2337083A1 - Compositions anti-apoptotiques comprenant la sous-unite r1 de la ribonucleotide-reductase du herpes simplex virus ou sa partie n-terminale et leurs applications - Google Patents

Compositions anti-apoptotiques comprenant la sous-unite r1 de la ribonucleotide-reductase du herpes simplex virus ou sa partie n-terminale et leurs applications Download PDF

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Publication number
CA2337083A1
CA2337083A1 CA002337083A CA2337083A CA2337083A1 CA 2337083 A1 CA2337083 A1 CA 2337083A1 CA 002337083 A CA002337083 A CA 002337083A CA 2337083 A CA2337083 A CA 2337083A CA 2337083 A1 CA2337083 A1 CA 2337083A1
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Prior art keywords
cells
hsv
protein
apoptotic
chx
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Abandoned
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CA002337083A
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English (en)
Inventor
Bernard Massie
Yves Langelier
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Centre de Recherche du Centre Hospitalier de lUniversite de Montreal
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Individual
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Priority to CA002337083A priority Critical patent/CA2337083A1/fr
Priority claimed from PCT/CA1999/000673 external-priority patent/WO2000007618A2/fr
Publication of CA2337083A1 publication Critical patent/CA2337083A1/fr
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
    • C12N2710/16622—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne une sous-unité R1 de la ribonucléotide réductase du herpès simplex virus (HSV) qui est exprimée juste après la réactivation virale, possède un domaine N-terminal d'environ 350 aminoacides de fonction inconnue. Nous avons démontré, à l'aide d'un système pouvant induire l'adénovirus (Ad), qu'une délétion complète de ce domaine produit une protéine cytotoxique. Ainsi, nous avons reporté que l'on pourrait éviter la mort apoptotique induite par cette R1 tronquée par coexpression de la longueur totale R1. L'activité anti-apoptotique R1 était justifiée car il a été démontré que l'expression de cette protéine en faible teneur peut bloquer complètement l'apoptose induite, soit par la famille du récepteur de TNF se manifestant en présence de cycloheximide (CHX), soit par coexpression Fas-L avec un recombinant Ad. Dans les deux cas, la protection n'était plus garantie lors de l'inhibition de la fonction tTA, la doxycycline analogue de la tétracycline immobilisant l'expression R1. Un niveau de R1 comprenant 0,005 % au total de protéine cellulaire s'est avéré suffisant pour assurer une demi-protection contre le TNF.alpha.+CHX. En surveillant l'activation caspase 8, soit par immunoblot avec un antisérum visualisant la proforme 56-kDa inactive et l'espèce 18-kDa active, soit par une épreuve in vitro au moyen d'ETD-AFC en tant que substrat fluorescent spécifique de caspase 8, nous avons découvert que la protéine R1 empêchait une forte activation de la caspase 8 induite par l'expression de TNF-.alpha.+CHX ou par Fas-L. Finalement, au moyen d'un mutant de délétion HSV-R1, ICP6.DELTA., nous avons obtenu la preuve directe de l'importance de HSV-R1 dans la protection des cellules infectées par HSV contre l'apoptose induite par la cytokine. Ces résultats montrent que la HSV R1 pourrait contribuer à la propagation virale, en sus de sa fonction de réduction essentielle pour la réactivation virale, en empêchant l'apoptose induite par le système immunitaire. Le domaine N-terminal est aussi anti-apoptotique que la protéine R1 dans son intégralité. Un agent anti-apoptotique et une composition le renfermant font aussi l'objet de cette invention.
CA002337083A 1998-07-31 1999-07-23 Compositions anti-apoptotiques comprenant la sous-unite r1 de la ribonucleotide-reductase du herpes simplex virus ou sa partie n-terminale et leurs applications Abandoned CA2337083A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA002337083A CA2337083A1 (fr) 1998-07-31 1999-07-23 Compositions anti-apoptotiques comprenant la sous-unite r1 de la ribonucleotide-reductase du herpes simplex virus ou sa partie n-terminale et leurs applications

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CA2239248 1998-07-31
CA2,239,248 1998-07-31
PCT/CA1999/000673 WO2000007618A2 (fr) 1998-07-31 1999-07-23 Compositions anti-apoptotiques comprenant la sous-unite r1 de la ribonucleotide-reductase du herpes simplex virus ou sa partie n-terminale et leurs applications
CA002337083A CA2337083A1 (fr) 1998-07-31 1999-07-23 Compositions anti-apoptotiques comprenant la sous-unite r1 de la ribonucleotide-reductase du herpes simplex virus ou sa partie n-terminale et leurs applications

Publications (1)

Publication Number Publication Date
CA2337083A1 true CA2337083A1 (fr) 2000-02-17

Family

ID=25680265

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002337083A Abandoned CA2337083A1 (fr) 1998-07-31 1999-07-23 Compositions anti-apoptotiques comprenant la sous-unite r1 de la ribonucleotide-reductase du herpes simplex virus ou sa partie n-terminale et leurs applications

Country Status (1)

Country Link
CA (1) CA2337083A1 (fr)

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