Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect
Min Gao, Richard E Nettles, Makonen Belema, Lawrence B Snyder, Van N Nguyen, Robert A Fridell, Michael H Serrano-Wu, David R Langley, Jin-Hua Sun, Donald R O'Boyle 2nd, Julie A Lemm, Chunfu Wang, Jay O Knipe, Caly Chien, Richard J Colonno, Dennis M Grasela, Nicholas A Meanwell, Lawrence G Hamann, Min Gao, Richard E Nettles, Makonen Belema, Lawrence B Snyder, Van N Nguyen, Robert A Fridell, Michael H Serrano-Wu, David R Langley, Jin-Hua Sun, Donald R O'Boyle 2nd, Julie A Lemm, Chunfu Wang, Jay O Knipe, Caly Chien, Richard J Colonno, Dennis M Grasela, Nicholas A Meanwell, Lawrence G Hamann
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.
Conflict of interest statement
The authors are or were, at the time this work was conducted, employees of Bristol-Myers Squibb.
Figures
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![Figure 2. The active inhibitor 1 binds…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7094952/bin/41586_2010_Article_BFnature08960_Fig2_HTML.jpg)
![Figure 3. Mean plasma concentration–time profile (time…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7094952/bin/41586_2010_Article_BFnature08960_Fig3_HTML.jpg)
![Figure 4. Mean change in log 10…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/7094952/bin/41586_2010_Article_BFnature08960_Fig4_HTML.jpg)
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Source: PubMed