title: Preclinical characterization of GSK2336805, a novel inhibitor of hepatitis C virus replication that selects for resistance in NS5A.
abstract: GSK2336805 is an inhibitor of hepatitis C virus (HCV) with picomolar activity on the standard genotype 1a, 1b, and 2a subgenomic replicons and exhibits a modest serum shift. GSK2336805 was not active on 22 RNA and DNA viruses that were profiled. We have identified changes in the N-terminal region of NS5A that cause a decrease in the activity of GSK2336805. These mutations in the genotype 1b replicon showed modest shifts in compound activity (<13-fold), while mutations identified in the genotype 1a replicon had a more dramatic impact on potency. GSK2336805 retained activity on chimeric replicons containing NS5A patient sequences from genotype 1 and patient and consensus sequences for genotypes 4 and 5 and part of genotype 6. Combination and cross-resistance studies demonstrated that GSK2336805 could be used as a component of a multidrug HCV regimen either with the current standard of care or in combination with compounds with different mechanisms of action that are still progressing through clinical development.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Walker
authors.forename: Renae
authors.initials: R
authors.lastname: Crosby
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.forename: Ermias
authors.initials: E
authors.lastname: Woldu
authors.forename: Jessica
authors.initials: J
authors.lastname: Vamathevan
authors.forename: Christian
authors.initials: C
authors.lastname: Voitenleitner
authors.forename: Shihyun
authors.initials: S
authors.lastname: You
authors.forename: Katja
authors.initials: K
authors.lastname: Remlinger
authors.forename: Maoshang
authors.initials: M
authors.lastname: Duan
authors.forename: Wieslaw
authors.initials: W
authors.lastname: Kazmierski
authors.forename: Robert
authors.initials: R
authors.lastname: Hamatake
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D012093:Replicon / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics
chemical_list: D000998:Antiviral Agents