Cargando…
Structure-Guided Design Affirms Inhibitors of Hepatitis C Virus p7 as a Viable Class of Antivirals Targeting Virion Release
Current interferon-based therapy for hepatitis C virus (HCV) infection is inadequate, prompting a shift toward combinations of direct-acting antivirals (DAA) with the first protease-targeted drugs licensed in 2012. Many compounds are in the pipeline yet primarily target only three viral proteins, na...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298801/ https://www.ncbi.nlm.nih.gov/pubmed/24022996 http://dx.doi.org/10.1002/hep.26685 |
_version_ | 1782353299004981248 |
---|---|
author | Foster, Toshana L Thompson, Gary S Kalverda, Arnout P Kankanala, Jayakanth Bentham, Matthew Wetherill, Laura F Thompson, Joseph Barker, Amy M Clarke, Dean Noerenberg, Marko Pearson, Arwen R Rowlands, David J Homans, Steven W Harris, Mark Foster, Richard Griffin, Stephen |
author_facet | Foster, Toshana L Thompson, Gary S Kalverda, Arnout P Kankanala, Jayakanth Bentham, Matthew Wetherill, Laura F Thompson, Joseph Barker, Amy M Clarke, Dean Noerenberg, Marko Pearson, Arwen R Rowlands, David J Homans, Steven W Harris, Mark Foster, Richard Griffin, Stephen |
author_sort | Foster, Toshana L |
collection | PubMed |
description | Current interferon-based therapy for hepatitis C virus (HCV) infection is inadequate, prompting a shift toward combinations of direct-acting antivirals (DAA) with the first protease-targeted drugs licensed in 2012. Many compounds are in the pipeline yet primarily target only three viral proteins, namely, NS3/4A protease, NS5B polymerase, and NS5A. With concerns growing over resistance, broadening the repertoire for DAA targets is a major priority. Here we describe the complete structure of the HCV p7 protein as a monomeric hairpin, solved using a novel combination of chemical shift and nuclear Overhauser effect (NOE)-based methods. This represents atomic resolution information for a full-length virus-coded ion channel, or “viroporin,” whose essential functions represent a clinically proven class of antiviral target exploited previously for influenza A virus therapy. Specific drug-protein interactions validate an allosteric site on the channel periphery and its relevance is demonstrated by the selection of novel, structurally diverse inhibitory small molecules with nanomolar potency in culture. Hit compounds represent a 10,000-fold improvement over prototypes, suppress rimantadine resistance polymorphisms at submicromolar concentrations, and show activity against other HCV genotypes. Conclusion: This proof-of-principle that structure-guided design can lead to drug-like molecules affirms p7 as a much-needed new target in the burgeoning era of HCV DAA. (Hepatology 2014;59:408–422) |
format | Online Article Text |
id | pubmed-4298801 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-42988012015-01-27 Structure-Guided Design Affirms Inhibitors of Hepatitis C Virus p7 as a Viable Class of Antivirals Targeting Virion Release Foster, Toshana L Thompson, Gary S Kalverda, Arnout P Kankanala, Jayakanth Bentham, Matthew Wetherill, Laura F Thompson, Joseph Barker, Amy M Clarke, Dean Noerenberg, Marko Pearson, Arwen R Rowlands, David J Homans, Steven W Harris, Mark Foster, Richard Griffin, Stephen Hepatology Viral Hepatitis Current interferon-based therapy for hepatitis C virus (HCV) infection is inadequate, prompting a shift toward combinations of direct-acting antivirals (DAA) with the first protease-targeted drugs licensed in 2012. Many compounds are in the pipeline yet primarily target only three viral proteins, namely, NS3/4A protease, NS5B polymerase, and NS5A. With concerns growing over resistance, broadening the repertoire for DAA targets is a major priority. Here we describe the complete structure of the HCV p7 protein as a monomeric hairpin, solved using a novel combination of chemical shift and nuclear Overhauser effect (NOE)-based methods. This represents atomic resolution information for a full-length virus-coded ion channel, or “viroporin,” whose essential functions represent a clinically proven class of antiviral target exploited previously for influenza A virus therapy. Specific drug-protein interactions validate an allosteric site on the channel periphery and its relevance is demonstrated by the selection of novel, structurally diverse inhibitory small molecules with nanomolar potency in culture. Hit compounds represent a 10,000-fold improvement over prototypes, suppress rimantadine resistance polymorphisms at submicromolar concentrations, and show activity against other HCV genotypes. Conclusion: This proof-of-principle that structure-guided design can lead to drug-like molecules affirms p7 as a much-needed new target in the burgeoning era of HCV DAA. (Hepatology 2014;59:408–422) BlackWell Publishing Ltd 2014-02 2013-12-24 /pmc/articles/PMC4298801/ /pubmed/24022996 http://dx.doi.org/10.1002/hep.26685 Text en Copyright © 2013 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Viral Hepatitis Foster, Toshana L Thompson, Gary S Kalverda, Arnout P Kankanala, Jayakanth Bentham, Matthew Wetherill, Laura F Thompson, Joseph Barker, Amy M Clarke, Dean Noerenberg, Marko Pearson, Arwen R Rowlands, David J Homans, Steven W Harris, Mark Foster, Richard Griffin, Stephen Structure-Guided Design Affirms Inhibitors of Hepatitis C Virus p7 as a Viable Class of Antivirals Targeting Virion Release |
title | Structure-Guided Design Affirms Inhibitors of Hepatitis C Virus p7 as a Viable Class of Antivirals Targeting Virion Release |
title_full | Structure-Guided Design Affirms Inhibitors of Hepatitis C Virus p7 as a Viable Class of Antivirals Targeting Virion Release |
title_fullStr | Structure-Guided Design Affirms Inhibitors of Hepatitis C Virus p7 as a Viable Class of Antivirals Targeting Virion Release |
title_full_unstemmed | Structure-Guided Design Affirms Inhibitors of Hepatitis C Virus p7 as a Viable Class of Antivirals Targeting Virion Release |
title_short | Structure-Guided Design Affirms Inhibitors of Hepatitis C Virus p7 as a Viable Class of Antivirals Targeting Virion Release |
title_sort | structure-guided design affirms inhibitors of hepatitis c virus p7 as a viable class of antivirals targeting virion release |
topic | Viral Hepatitis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298801/ https://www.ncbi.nlm.nih.gov/pubmed/24022996 http://dx.doi.org/10.1002/hep.26685 |
work_keys_str_mv | AT fostertoshanal structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT thompsongarys structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT kalverdaarnoutp structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT kankanalajayakanth structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT benthammatthew structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT wetherilllauraf structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT thompsonjoseph structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT barkeramym structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT clarkedean structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT noerenbergmarko structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT pearsonarwenr structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT rowlandsdavidj structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT homansstevenw structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT harrismark structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT fosterrichard structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease AT griffinstephen structureguideddesignaffirmsinhibitorsofhepatitiscvirusp7asaviableclassofantiviralstargetingvirionrelease |