title: Discovery and development of hepatitis C virus NS5A replication complex inhibitors.
abstract: Lead inhibitors that target the function of the hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration of antiviral activity in HCV-infected subjects by the HCV NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest in this mechanistic approach. In this Perspective, we summarize the medicinal chemistry studies that led to the discovery of 1 and other chemotypes for which resistance maps to the NS5A protein and provide synopses of the profiles of many of the compounds currently in clinical trials. We also summarize what is currently known about the NS5A protein and the studies using NS5A RCIs and labeled analogues that are helping to illuminate aspects of both protein function and inhibitor interaction. We conclude with a synopsis of the results of notable clinical trials with HCV NS5A RCIs.
authors.affiliation: Department of Discovery Chemistry, ‡Department of Virology Discovery, and §Department of Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Makonen
authors.initials: M
authors.lastname: Belema
authors.forename: Omar D
authors.initials: OD
authors.lastname: Lopez
authors.forename: John A
authors.initials: JA
authors.lastname: Bender
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Romine
authors.forename: Denis R
authors.initials: DR
authors.lastname: St Laurent
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.forename: Donald R
authors.initials: DR
authors.lastname: O'Boyle
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fridell
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
mesh_terms: D055808:Drug Discovery; D016174:Hepacivirus / Q000378:metabolism* / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase