Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.
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.
Gao
Min
M
Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.
Nettles
Richard E
RE
Belema
Makonen
M
Snyder
Lawrence B
LB
Nguyen
Van N
VN
Fridell
Robert A
RA
Serrano-Wu
Michael H
MH
Langley
David R
DR
Sun
Jin-Hua
JH
O'Boyle
Donald R
DR
Lemm
Julie A
JA
Wang
Chunfu
C
Knipe
Jay O
JO
Chien
Caly
C
Colonno
Richard J
RJ
Grasela
Dennis M
DM
Meanwell
Nicholas A
NA
Hamann
Lawrence G
LG
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
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
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