title: Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors.
abstract: In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two α-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the α-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the α-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses.
authors.affiliation: Department of Clinical Virology, Gilead Sciences, 333 Lakeside Dr., Foster City, CA 94404, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bae
authors.forename: Siu-Chi
authors.initials: SC
authors.lastname: Sun
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qi
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Chen
authors.forename: Karin
authors.initials: K
authors.lastname: Ku
authors.forename: Angela
authors.initials: A
authors.lastname: Worth
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Wong
authors.forename: Jeanette
authors.initials: J
authors.lastname: Harris
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003521:Cyclopropanes; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D054833:Isoindoles; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000069616:Simeprevir; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D009842:Oligopeptides; D011480:Protease Inhibitors; D013449:Sulfonamides; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; C553752:danoprevir; D011392:Proline; D000069616:Simeprevir; C540393:vaniprevir; D007930:Leucine