title: Preclinical characterization of JTK-853, a novel nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase.
abstract: JTK-853 is a novel piperazine derivative nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase. JTK-853 showed potent inhibitory activity against genotype 1 HCV polymerase, with a 50% inhibitory concentration in the nanomolar range, and showed potent antiviral activity against the genotype 1b replicon, with a 50% effective concentration of 0.035 μM. The presence of human serum at up to 40% had little effect on the antiviral activity of JTK-853. Structure analysis of HCV polymerase with JTK-853 revealed that JTK-853 associates with the palm site and β-hairpin region of HCV polymerase, and JTK-853 showed decreased antiviral activity against HCV replicons bearing the resistance mutations C316Y, M414T, Y452H, and L466V in the palm site region of HCV polymerase. JTK-853 showed an additive combination effect with other DAAs (direct antiviral agents), such as nucleoside polymerase inhibitor, thumb pocket-binding nonnucleoside polymerase inhibitor, NS5A inhibitor, and protease inhibitor. Collectively, these data demonstrate that JTK-853 is a potent and novel nonnucleoside palm site-binding HCV polymerase inhibitor, suggesting JTK-853 as a potentially useful agent in combination with other DAAs for treatment of HCV infections.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco, Inc., Takatsuki, Osaka, Japan.
authors.forename: Izuru
authors.initials: I
authors.lastname: Ando
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Adachi
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogura
authors.forename: Yukiyo
authors.initials: Y
authors.lastname: Toyonaga
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Abe
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kamada
authors.forename: Toru
authors.initials: T
authors.lastname: Noguchi
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors
chemical_list: D000998:Antiviral Agents; D010879:Piperazines; D017361:Viral Nonstructural Proteins; D012324:RNA-Dependent RNA Polymerase; C578010:JTK-853