Publication Date:
2010-04-23
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Min -- Nettles, Richard E -- Belema, Makonen -- Snyder, Lawrence B -- Nguyen, Van N -- Fridell, Robert A -- Serrano-Wu, Michael H -- Langley, David R -- Sun, Jin-Hua -- O'Boyle, Donald R 2nd -- Lemm, Julie A -- Wang, Chunfu -- Knipe, Jay O -- Chien, Caly -- Colonno, Richard J -- Grasela, Dennis M -- Meanwell, Nicholas A -- Hamann, Lawrence G -- England -- Nature. 2010 May 6;465(7294):96-100. doi: 10.1038/nature08960. Epub 2010 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20410884" target="_blank"〉PubMed〈/a〉
Keywords:
Adolescent
;
Adult
;
Animals
;
Antiviral Agents/blood/chemistry/*pharmacology/therapeutic use
;
Cell Line
;
Cercopithecus aethiops
;
Drug Resistance, Viral
;
Female
;
Genotype
;
HeLa Cells
;
Hepacivirus/*drug effects
;
Hepatitis C/drug therapy/virology
;
Humans
;
Imidazoles/blood/chemistry/*pharmacology
;
Inhibitory Concentration 50
;
Male
;
Middle Aged
;
Time Factors
;
Vero Cells
;
Viral Load/drug effects
;
Viral Nonstructural Proteins/*antagonists & inhibitors
;
Young Adult
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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