title: Comparison of daclatasvir resistance barriers on NS5A from hepatitis C virus genotypes 1 to 6: implications for cross-genotype activity.
abstract: A comparison of the daclatasvir (DCV [BMS-790052]) resistance barrier on authentic or hybrid replicons containing NS5A from hepatitis C virus (HCV) genotypes 1 to 6 (GT-1 to -6) was completed using a replicon elimination assay. The data indicated that genotype 1b (GT-1b) has the highest relative resistance barrier and genotype 2a (GT-2a M31) has the lowest. The rank order of resistance barriers to DCV was 1b>4a≥5a>6a≅1a>2a JFH>3a>2a M31. Importantly, DCV in combination with a protease inhibitor (PI) eliminated GT-2a M31 replicon RNA at a clinically relevant concentration. Previously, we reported the antiviral activity and resistance profiles of DCV on HCV genotypes 1 to 4 evaluated in the replicon system. Here, we report the antiviral activity and resistance profiles of DCV against hybrid replicons with NS5A sequences derived from HCV GT-5a and GT-6a clinical isolates. DCV was effective against both GT-5a and -6a hybrid replicon cell lines (50% effective concentrations [EC50s] ranging from 3 to 7 pM for GT-5a, and 74 pM for GT-6a). Resistance selection identified amino acid substitutions in the N-terminal domain of NS5A. For GT-5a, L31F and L31V, alone or in combination with K56R, were the major resistance variants (EC50s ranging from 2 to 40 nM). In GT-6a, Q24H, L31M, P32L/S, and T58A/S were identified as resistance variants (EC50s ranging from 2 to 250 nM). The in vitro data suggest that DCV has the potential to be an effective agent for HCV genotypes 1 to 6 when used in combination therapy.
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA chunfu.wang@bms.com.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Jia
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Donald R
authors.initials: DR
authors.lastname: O'Boyle
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Rigat
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Valera
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Nower
authors.affiliation: Applied Genomics, Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Applied Genomics, Bristol-Myers Squibb Research and Development, Hopewell, New Jersey, USA.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Kienzle
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Roberts
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.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fridell
mesh_terms: D019943:Amino Acid Substitution / Q000187:drug effects / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology; D002219:Carbamates; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D007093:Imidazoles / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines; D012093:Replicon / Q000187:drug effects / Q000235:genetics; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011480:Protease Inhibitors; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir