title: Identification and characterization of mutations conferring resistance to an HCV RNA-dependent RNA polymerase inhibitor in vitro.
abstract: Compound A-837093, a non-nucleoside HCV RNA-dependent RNA polymerase inhibitor, displayed nanomolar potencies against HCV genotypes 1a and 1b replicons. It also exhibited an excellent metabolic profile and achieved high plasma and liver concentrations in animals. In order to characterize the development of resistance to this anti-HCV agent, HCV subgenomic 1b strain N replicon cells were cultured in the presence of A-837093 with G418. Mutations S368A, Y448H, G554D, Y555C, and D559G in the NS5B polymerase gene were identified that led to substantial decreases in the susceptibilities of 1b genotype replicons to the inhibitor A-837093. However, the resistant mutants remained susceptible to HCV protease inhibitor BILN-2061 and alpha interferon as well as to a different class of non-nucleoside HCV polymerase inhibitor. In addition, each single resistant mutation identified significantly reduced the replication capacity of mutant compared to wild-type replicon. These findings provide a strategic guide for the future development of non-nucleoside inhibitors of HCV NS5B polymerase.
authors.affiliation: Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA. liangjun.lu@abbott.com
authors.forename: Liangjun
authors.initials: L
authors.lastname: Lu
authors.forename: Tatyana
authors.initials: T
authors.lastname: Dekhtyar
authors.forename: Sherie
authors.initials: S
authors.lastname: Masse
authors.forename: Ron
authors.initials: R
authors.lastname: Pithawalla
authors.forename: Preethi
authors.initials: P
authors.lastname: Krishnan
authors.forename: Wenping
authors.initials: W
authors.lastname: He
authors.forename: Teresa
authors.initials: T
authors.lastname: Ng
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Koev
authors.forename: Kent
authors.initials: K
authors.lastname: Stewart
authors.forename: Dan
authors.initials: D
authors.lastname: Larson
authors.forename: Todd
authors.initials: T
authors.lastname: Bosse
authors.forename: Rolf
authors.initials: R
authors.lastname: Wagner
authors.forename: Tami
authors.initials: T
authors.lastname: Pilot-Matias
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.forename: Akhteruzumman
authors.initials: A
authors.lastname: Molla
mesh_terms: D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005814:Genes, Viral / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D012093:Replicon / Q000235:genetics; D014764:Viral Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D014779:Virus Replication
chemical_list: D004791:Enzyme Inhibitors; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase