Identification and characterization of mutations conferring resistance to an HCV RNA-dependent RNA polymerase inhibitor in vitro.
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.
Lu
Liangjun
L
Abbott Laboratories, Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA. liangjun.lu@abbott.com
Dekhtyar
Tatyana
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Masse
Sherie
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Pithawalla
Ron
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Krishnan
Preethi
P
He
Wenping
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Ng
Teresa
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Koev
Gennadiy
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Stewart
Kent
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Larson
Dan
D
Bosse
Todd
T
Wagner
Rolf
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Pilot-Matias
Tami
T
Mo
Hongmei
H
Molla
Akhteruzumman
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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
D004791:Enzyme Inhibitors; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase