title: Potency and resistance analysis of hepatitis C virus NS5B polymerase inhibitor BMS-791325 on all major genotypes.
abstract: BMS-791325 is a hepatitis C virus (HCV) inhibitor binding to the thumb domain of the NS5B RNA-dependent RNA polymerase. BMS-791325 is well characterized in genotype 1 (GT1) and exhibits good inhibitory activity (50% effective concentration [EC50], <10 nM) against hybrid replicons containing patient NS5B sequences from GT3a, -4a, and -5a while potency against GT2 is significantly reduced (J. A. Lemm et al., Antimicrob. Agents Chemother. 58:3485-3495, 2014, doi:http://dx.doi.org/10.1128/AAC.02495-13). BMS-791325 potency against GT6a hybrid replicons is more variable, with two of three hybrid clones having EC50s similar to that for GT1 while a third patient clone was ∼ 10 times less susceptible to BMS-791325. To characterize the resistance profile of BMS-791325 beyond GT1, curing studies were performed across GT1a and -3a to -6a and demonstrated that GT1a has the highest resistance barrier versus BMS-791325 while GT6a has the lowest. Selection of GT3 to -6 NS5B chimeric replicon cells at different concentrations of BMS-791325 revealed substitutions in the thumb domain of NS5B at residues 494 and 495 that conferred different levels of resistance to BMS-791325 but remained susceptible to NS5A or NS3 protease inhibitors. In addition, we demonstrate that the reduced potency of BMS-791325 against one GT6a patient is due to an A494 polymorphism present in ∼ 21% of sequences in the European HCV database. The results from this report suggest that BMS-791325 is a candidate for combination treatment of HCV GT3 to -6 chronic infections, and the resistance profiles identified will provide useful information for future clinical development.
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Mengping
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Tuttle
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA Julie.Lemm@bms.com.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
mesh_terms: D019943:Amino Acid Substitution; D001552:Benzazepines / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D024882:Drug Resistance, Viral / Q000235:genetics*; D015870:Gene Expression; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012093:Replicon; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D001552:Benzazepines; D007211:Indoles; D019384:Nucleic Acid Synthesis Inhibitors; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C587012:8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase