title: Tegobuvir (GS-9190) potency against HCV chimeric replicons derived from consensus NS5B sequences from genotypes 2b, 3a, 4a, 5a, and 6a.
abstract: With the exception of nucleoside analogs, few direct acting antivirals in clinical development are active across the six major hepatitis C virus genotypes. We report novel consensus sequence chimeras for genotypes 2b, 3a, 4a, 5a, and 6a NS5B and show variable susceptibilities over a panel of NS5B inhibitors. Tegobuvir (GS-9190) had EC(50)s of <16 nM against genotype 1 and >100 nM for other genotypes tested here. An NS5B F445C mutation engineered into the GT3a, 4a, and 6a chimeric replicons lowered the tegobuvir EC(50) to levels comparable to those for genotype 1a, but did not considerably alter the EC(50) of site 2 or nucleoside analog inhibitors. These data support the use of HCV chimeras in profiling direct acting antivirals across genotypes and specifically determines the impact of the C445F NS5B polymorphism on tegobuvir potency against genotypes 3a, 4a, and 6a.
authors.affiliation: Department of Clinical Virology, Gilead Sciences, Inc., Foster City, CA 94404, USA. kelly.wong@gilead.com
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Wong
authors.forename: Simin
authors.initials: S
authors.lastname: Xu
authors.forename: Ross
authors.initials: R
authors.lastname: Martin
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D016384:Consensus Sequence; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D012093:Replicon / Q000187:drug effects*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011687:Purines; D011724:Pyridazines; D017361:Viral Nonstructural Proteins; C571890:tegobuvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase