title: Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.
abstract: The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.
authors.affiliation: Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Richard E
authors.initials: RE
authors.lastname: Nettles
authors.forename: Makonen
authors.initials: M
authors.lastname: Belema
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Snyder
authors.forename: Van N
authors.initials: VN
authors.lastname: Nguyen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fridell
authors.forename: Michael H
authors.initials: MH
authors.lastname: Serrano-Wu
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Jin-Hua
authors.initials: JH
authors.lastname: Sun
authors.forename: Donald R
authors.initials: DR
authors.lastname: O'Boyle
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lemm
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wang
authors.forename: Jay O
authors.initials: JO
authors.lastname: Knipe
authors.forename: Caly
authors.initials: C
authors.lastname: Chien
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Colonno
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Meanwell
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002219:Carbamates; D002460:Cell Line; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D006367:HeLa Cells; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives; D014709:Vero Cells; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir
references.citation: Nature. 2005 May 19;435(7040):374-9
references.pmid: 15902263
references.citation: N Engl J Med. 2001 Jul 5;345(1):41-52
references.pmid: 11439948
references.citation: Expert Opin Drug Discov. 2008 Jun 1;3(6):671-676
references.pmid: 19750206
references.citation: Expert Opin Drug Discov. 2009 Mar;4(3):293-314
references.pmid: 23489127
references.citation: J Virol. 2004 Aug;78(15):7904-15
references.pmid: 15254163
references.citation: Antimicrob Agents Chemother. 2005 Apr;49(4):1346-53
references.pmid: 15793110
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9739-40
references.pmid: 15998731
references.citation: J Biol Chem. 2006 Apr 14;281(15):9833-6
references.pmid: 16407182
references.citation: Nature. 2005 Aug 18;436(7053):953-60
references.pmid: 16107835
references.citation: Nat Rev Drug Discov. 2007 Dec;6(12):991-1000
references.pmid: 18049473
references.citation: J Virol. 2009 May;83(9):4395-403
references.pmid: 19244328
references.citation: J Virol. 2003 Jun;77(12):6753-60
references.pmid: 12767995
references.citation: Nature. 2004 Dec 16;432(7019):846-54
references.pmid: 15602550
references.citation: Hepatology. 2007 Oct;46(4):1026-33
references.pmid: 17600342
references.citation: Microbes Infect. 2002 Oct;4(12):1219-25
references.pmid: 12467763
references.citation: Science. 1999 Jul 2;285(5424):110-3
references.pmid: 10390360
references.citation: Nat Rev Drug Discov. 2002 Nov;1(11):911-6
references.pmid: 12415250
references.citation: Proc Natl Acad Sci U S A. 2006 May 9;103(19):7408-13
references.pmid: 16651538
references.citation: N Engl J Med. 2006 Dec 7;355(23):2444-51
references.pmid: 17151366
references.citation: J Virol. 2010 Jan;84(1):482-91
references.pmid: 19812153
references.citation: Recent Pat Antiinfect Drug Discov. 2008 Jun;3(2):77-92
references.pmid: 18673121
references.citation: World J Gastroenterol. 2008 Jun 21;14(23):3621-7
references.pmid: 18595128