title: Mechanistic characterization of GS-9190 (Tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase.
abstract: GS-9190 (Tegobuvir) is a novel imidazopyridine inhibitor of hepatitis C virus (HCV) RNA replication in vitro and has demonstrated potent antiviral activity in patients chronically infected with genotype 1 (GT1) HCV. GS-9190 exhibits reduced activity against GT2a (JFH1) subgenomic replicons and GT2a (J6/JFH1) infectious virus, suggesting that the compound's mechanism of action involves a genotype-specific viral component. To further investigate the GS-9190 mechanism of action, we utilized the susceptibility differences between GT1b and GT2a by constructing a series of replicon chimeras where combinations of 1b and 2a nonstructural proteins were encoded within the same replicon. The antiviral activities of GS-9190 against the chimeric replicons were reduced to levels comparable to that of the wild-type GT2a replicon in chimeras expressing GT2a NS5B. GT1b replicons in which the β-hairpin region (amino acids 435 to 455) was replaced by the corresponding sequence of GT2a were markedly less susceptible to GS-9190, indicating the importance of the thumb subdomain of the polymerase in this effect. Resistance selection in GT1b replicon cells identified several mutations in NS5B (C316Y, Y448H, Y452H, and C445F) that contributed to the drug resistance phenotype. Reintroduction of these mutations into wild-type replicons conferred resistance to GS-9190, with the number of NS5B mutations correlating with the degree of resistance. Analysis of GS-9190 cross-resistance against previously reported NS5B drug-selected mutations showed that the resistance pattern of GS-9190 is different from other nonnucleoside inhibitors. Collectively, these data demonstrate that GS-9190 represents a novel class of nonnucleoside polymerase inhibitors that interact with NS5B likely through involvement of the β-hairpin in the thumb subdomain.
authors: Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, USA.
authors: I-Hung
authors: IH
authors: Shih
authors: Inge
authors: I
authors: Vliegen
authors: Betty
authors: B
authors: Peng
authors: Huiling
authors: H
authors: Yang
authors: Christy
authors: C
authors: Hebner
authors: Jan
authors: J
authors: Paeshuyse
authors: Gerhard
authors: G
authors: Pürstinger
authors: Martijn
authors: M
authors: Fenaux
authors: Yang
authors: Y
authors: Tian
authors: Eric
authors: E
authors: Mabery
authors: Xiaoping
authors: X
authors: Qi
authors: Gina
authors: G
authors: Bahador
authors: Matthew
authors: M
authors: Paulson
authors: Laura S
authors: LS
authors: Lehman
authors: Steven
authors: S
authors: Bondy
authors: Winston
authors: W
authors: Tse
authors: Hans
authors: H
authors: Reiser
authors: William A
authors: WA
authors: Lee
authors: Uli
authors: U
authors: Schmitz
authors: Johan
authors: J
authors: Neyts
authors: Weidong
authors: W
authors: Zhong
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D015394:Molecular Structure; D009154:Mutation; D010957:Plasmids / Q000235:genetics; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011687:Purines; D011724:Pyridazines; D017361:Viral Nonstructural Proteins; C571890:tegobuvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase