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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(1). Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological resp...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094952/ https://www.ncbi.nlm.nih.gov/pubmed/20410884 http://dx.doi.org/10.1038/nature08960 |
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author | 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 II, Donald R. Lemm, Julie A. Wang, Chunfu Knipe, Jay O. Chien, Caly Colonno, Richard J. Grasela, Dennis M. Meanwell, Nicholas A. Hamann, Lawrence G. |
author_facet | 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 II, Donald R. Lemm, Julie A. Wang, Chunfu Knipe, Jay O. Chien, Caly Colonno, Richard J. Grasela, Dennis M. Meanwell, Nicholas A. Hamann, Lawrence G. |
author_sort | Gao, Min |
collection | PubMed |
description | The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people(1). 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 virus(2,3). 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 NS5B(4). 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. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nature08960) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7094952 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-70949522020-03-26 Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect 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 II, Donald R. Lemm, Julie A. Wang, Chunfu Knipe, Jay O. Chien, Caly Colonno, Richard J. Grasela, Dennis M. Meanwell, Nicholas A. Hamann, Lawrence G. Nature Article The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people(1). 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 virus(2,3). 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 NS5B(4). 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. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nature08960) contains supplementary material, which is available to authorized users. Nature Publishing Group UK 2010-04-21 2010 /pmc/articles/PMC7094952/ /pubmed/20410884 http://dx.doi.org/10.1038/nature08960 Text en © Macmillan Publishers Limited. All rights reserved 2010 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Article 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 II, Donald R. Lemm, Julie A. Wang, Chunfu Knipe, Jay O. Chien, Caly Colonno, Richard J. Grasela, Dennis M. Meanwell, Nicholas A. Hamann, Lawrence G. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect |
title | Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect |
title_full | Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect |
title_fullStr | Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect |
title_full_unstemmed | Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect |
title_short | Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect |
title_sort | chemical genetics strategy identifies an hcv ns5a inhibitor with a potent clinical effect |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094952/ https://www.ncbi.nlm.nih.gov/pubmed/20410884 http://dx.doi.org/10.1038/nature08960 |
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