title: Comparison of HCV NS3 protease and NS5B polymerase inhibitor activity in 1a, 1b and 2a replicons and 2a infectious virus.
abstract: The hepatitis C virus infection system represents an important new tool for drug discovery. In this study, we compared the in vitro antiviral efficacy of several NS3 and NS5B inhibitors in genotype 1a, 1b, and 2a replicons and in the 2a infectious virus system. The nucleoside inhibitor 2'-C-methyl adenosine showed similar efficacy in each system tested. Three non-nucleoside inhibitors had small differences in potency between genotype 1a and 1b. In contrast, there was a dramatic loss of potency for these non-nucleoside inhibitors in the genotype 2a replicon, 2a infectious virus, and 2a NS5B biochemical assays. The protease inhibitor BILN-2061 had similar efficacy against 1a and 1b replicons but was 61-109-fold less potent against the 2a replicon and virus, respectively. VX-950, a covalent protease inhibitor, had similar efficacy (<3-fold changes in EC(50)) regardless of genotype or subtype. Importantly, we observed a significant correlation (p<0.0001) in antiviral potency between the 2a replicon and 2a infectious virus for all classes of compounds tested.
authors.affiliation: Gilead Sciences, Inc., Foster City, CA 94404, USA. Matthew.Paulson@gilead.com
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Paulson
authors.forename: Huiling
authors.initials: H
authors.lastname: Yang
authors.forename: I-hung
authors.initials: IH
authors.lastname: Shih
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Feng
authors.forename: Eric M
authors.initials: EM
authors.lastname: Mabery
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Robinson
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhong
authors.forename: William E
authors.initials: WE
authors.lastname: Delaney
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D016174:Hepacivirus / Q000145:classification* / Q000187:drug effects*; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase