Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect

Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect


Min Gao1, Richard E. Nettles2, Makonen Belema3, Lawrence B. Snyder3, Van N. Nguyen3, Robert A. Fridell1, Michael H. Serrano-Wu3, David R. Langley4, Jin-Hua Sun1, Donald R. O’Boyle II1, Julie A. Lemm1, Chunfu Wang1, Jay O. Knipe5, Caly Chien2, Richard J. Colonno1, Dennis M. Grasela2, Nicholas A. Meanwell3 & Lawrence G. Hamann3

Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA
Department of Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA
Department of Discovery Chemistry,
Department of Computer-Aided Drug Design,
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA
Correspondence to: Nicholas A. Meanwell3 Email: Nicholas.Meanwell@bms.com


Top of page
Abstract
The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people1. Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus2, 3. 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 NS5B4. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC50) 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 log10 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.

Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA
Department of Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA
Department of Discovery Chemistry,
Department of Computer-Aided Drug Design,
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA
Correspondence to: Nicholas A. Meanwell3 Email: Nicholas.Meanwell@bms.com