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Biochemical study of the comparative inhibition of hepatitis C virus RNA polymerase by VX-222 and filibuvir
- Source :
- Antimicrobial agents and chemotherapy. 56(2)
- Publication Year :
- 2011
-
Abstract
- Filibuvir and VX-222 are nonnucleoside inhibitors (NNIs) that bind to the thumb II allosteric pocket of the hepatitis C virus (HCV) RNA-dependent RNA polymerase. Both compounds have shown significant promise in clinical trials and, therefore, it is relevant to better understand their mechanisms of inhibition. In our study, filibuvir and VX-222 inhibited the 1b/Con1 HCV subgenomic replicon, with 50% effective concentrations (EC 50 s) of 70 nM and 5 nM, respectively. Using several RNA templates in biochemical assays, we found that both compounds preferentially inhibited primer-dependent RNA synthesis but had either no or only modest effects on de novo -initiated RNA synthesis. Filibuvir and VX-222 bind to the HCV polymerase with dissociation constants of 29 and 17 nM, respectively. Three potential resistance mutations in the thumb II pocket were analyzed for effects on inhibition by the two compounds. The M423T substitution in the RNA polymerase was at least 100-fold more resistant to filibuvir in the subgenomic replicon and in the enzymatic assays. This resistance was the result of a 250-fold loss in the binding affinity ( K d ) of the mutated enzyme to filibuvir. In contrast, the inhibitory activity of VX-222 was only modestly affected by the M423T substitution but more significantly affected by an I482L substitution.
- Subjects :
- Models, Molecular
Hepatitis C virus
RNA-dependent RNA polymerase
Hepacivirus
Thiophenes
Biology
medicine.disease_cause
Antiviral Agents
chemistry.chemical_compound
RNA polymerase
Cell Line, Tumor
Drug Resistance, Viral
medicine
Humans
Pharmacology (medical)
Replicon
Binding site
Enzyme Inhibitors
Polymerase
Pharmacology
chemistry.chemical_classification
Binding Sites
RNA
Templates, Genetic
Triazoles
Cyclohexanols
RNA-Dependent RNA Polymerase
Molecular biology
Infectious Diseases
Enzyme
chemistry
Pyrones
Mutation
biology.protein
RNA, Viral
Subjects
Details
- ISSN :
- 10986596
- Volume :
- 56
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Antimicrobial agents and chemotherapy
- Accession number :
- edsair.doi.dedup.....4025ff71f68f4de3bd33cbbf4eb799a5