General Catalytic Deficiency of Hepatitis C Virus RNA Polymerase with an S282T Mutation and Mutually Exclusive Resistance towards 2'-Modified Nucleotide Analogues
| Autor: | Bruno Canard, Hélène Dutartre, Joëlle Boretto, Cécile Bussetta |
|---|---|
| Přispěvatelé: | Oncogenèse rétrovirale – Retroviral Oncogenesis (OR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Oncogenèse rétrovirale – Retroviral Oncogenesis |
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Hepatitis C virus viruses RNA-dependent RNA polymerase Cytidine Hepacivirus Biology medicine.disease_cause Antiviral Agents 03 medical and health sciences chemistry.chemical_compound RNA polymerase Drug Resistance Viral medicine Humans Pharmacology (medical) Replicon NS5B Polymerase 030304 developmental biology Pharmacology 0303 health sciences Binding Sites Nucleotides 030306 microbiology RNA RNA-Dependent RNA Polymerase Molecular biology 3. Good health Kinetics Infectious Diseases chemistry RNA editing Mutation [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology biology.protein RNA Viral |
| Zdroj: | Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, 2006, 50 (12), pp.4161-4169. ⟨10.1128/AAC.00433-06⟩ Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2006, 50 (12), pp.4161-4169. ⟨10.1128/AAC.00433-06⟩ |
| ISSN: | 0066-4804 1098-6596 |
| DOI: | 10.1128/AAC.00433-06⟩ |
| Popis: | The hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B is an important target for antiviral therapies. NS5B is able to initiate viral RNA synthesis de novo and then switch to a fast and processive RNA elongation synthesis mode. The nucleotide analogue 2′- C -methyl CTP (2′- C -Me-CTP) is the active metabolite of NM283, a drug currently in clinical phase II trials. The resistance mutation S282T can be selected in HCV replicon studies. Likewise, 2′- O -Me nucleotides are active both against the purified polymerase and in replicon studies. We have determined the molecular mechanism by which the S282T mutation confers resistance to 2′-modified nucleotide analogues. 2′- C -Me-CTP is no longer incorporated during the initiation step of RNA synthesis and is discriminated 21-fold during RNA elongation by the NS5B S282T mutant. Strikingly, 2′- O -methyl CTP sensitivity does not change during initiation, but the analogue is no longer incorporated during elongation. This mutually exclusive resistance mechanism suggests not only that “2′-conformer” analogues target distinct steps in RNA synthesis but also that these analogues have interesting potential in combination therapies. In addition, the presence of the S282T mutation induces a general cost in terms of polymerase efficiency that may translate to decreased viral fitness: natural nucleotides become 5- to 20-fold less efficiently incorporated into RNA by the NS5B S282T mutant. As in the case for human immunodeficiency virus, our results might provide a mechanistic basis for the rational combination of drugs for low-fitness viruses. |
| Databáze: | OpenAIRE |
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