title: Characterizations of HCV NS5A replication complex inhibitors.
abstract: The hepatitis C virus NS5A protein is an established and clinically validated target for antiviral intervention by small molecules. Characterizations are presented of compounds identified as potent inhibitors of HCV replication to provide insight into structural elements that interact with the NS5A protein. UV-activated cross linking and affinity isolation was performed with one series to probe the physical interaction between the inhibitors and the NS5A protein expressed in HCV replicon cells. Resistance mapping with the second series was used to determine the functional impact of specific inhibitor subdomains on the interaction with NS5A. The data provide evidence for a direct high-affinity interaction between these inhibitors and the NS5A protein, with the interaction dependent on inhibitor stereochemistry. The functional data supports a model of inhibition that implicates inhibitor binding by covalently combining distinct pharmacophores across an NS5A dimer interface to achieve maximal inhibition of HCV replication.
authors.affiliation: Bristol-Myers Squibb Research and Development, Department of Virology Discovery, 5 Research Parkway, Wallingford, CT 06492, USA. oboyled@bms.com
authors.forename: Donald R
authors.initials: DR
authors.lastname: O'Boyle Ii
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nower
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fridell
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wang
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Romine
authors.forename: Makonen
authors.initials: M
authors.lastname: Belema
authors.forename: Van N
authors.initials: VN
authors.lastname: Nguyen
authors.forename: Denis R St
authors.initials: DR
authors.lastname: Laurent
authors.forename: Michael
authors.initials: M
authors.lastname: Serrano-Wu
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Snyder
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Min
authors.initials: M
authors.lastname: Gao
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D011485:Protein Binding; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Antiviral; Covalent attachment; Daclatasvir; HCV; NS5A dimer; NS5A replication complex inhibitor