Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy
Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or ‘viroporins’, contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton...
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Format: | Article |
Language: | English |
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eLife Sciences Publications Ltd
2020-11-01
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Series: | eLife |
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Online Access: | https://elifesciences.org/articles/52555 |
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doaj-3401ae4371944442844f8b367aa9f459 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Joseph Shaw Rajendra Gosain Monoj Mon Kalita Toshana L Foster Jayakanth Kankanala D Ram Mahato Sonia Abas Barnabas J King Claire Scott Emma Brown Matthew J Bentham Laura Wetherill Abigail Bloy Adel Samson Mark Harris Jamel Mankouri David J Rowlands Andrew Macdonald Alexander W Tarr Wolfgang B Fischer Richard Foster Stephen Griffin |
spellingShingle |
Joseph Shaw Rajendra Gosain Monoj Mon Kalita Toshana L Foster Jayakanth Kankanala D Ram Mahato Sonia Abas Barnabas J King Claire Scott Emma Brown Matthew J Bentham Laura Wetherill Abigail Bloy Adel Samson Mark Harris Jamel Mankouri David J Rowlands Andrew Macdonald Alexander W Tarr Wolfgang B Fischer Richard Foster Stephen Griffin Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy eLife hepatitis c virus p7 viroporin antiviral drugs virion egress virus entry |
author_facet |
Joseph Shaw Rajendra Gosain Monoj Mon Kalita Toshana L Foster Jayakanth Kankanala D Ram Mahato Sonia Abas Barnabas J King Claire Scott Emma Brown Matthew J Bentham Laura Wetherill Abigail Bloy Adel Samson Mark Harris Jamel Mankouri David J Rowlands Andrew Macdonald Alexander W Tarr Wolfgang B Fischer Richard Foster Stephen Griffin |
author_sort |
Joseph Shaw |
title |
Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy |
title_short |
Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy |
title_full |
Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy |
title_fullStr |
Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy |
title_full_unstemmed |
Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy |
title_sort |
rationally derived inhibitors of hepatitis c virus (hcv) p7 channel activity reveal prospect for bimodal antiviral therapy |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2020-11-01 |
description |
Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or ‘viroporins’, contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery. We describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery. |
topic |
hepatitis c virus p7 viroporin antiviral drugs virion egress virus entry |
url |
https://elifesciences.org/articles/52555 |
work_keys_str_mv |
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doaj-3401ae4371944442844f8b367aa9f4592021-05-05T21:41:51ZengeLife Sciences Publications LtdeLife2050-084X2020-11-01910.7554/eLife.52555Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapyJoseph Shaw0Rajendra Gosain1Monoj Mon Kalita2https://orcid.org/0000-0002-8037-8489Toshana L Foster3Jayakanth Kankanala4D Ram Mahato5https://orcid.org/0000-0002-1121-7761Sonia Abas6Barnabas J King7https://orcid.org/0000-0001-8432-2282Claire Scott8Emma Brown9Matthew J Bentham10Laura Wetherill11Abigail Bloy12Adel Samson13Mark Harris14Jamel Mankouri15David J Rowlands16Andrew Macdonald17Alexander W Tarr18https://orcid.org/0000-0003-1009-0823Wolfgang B Fischer19Richard Foster20Stephen Griffin21https://orcid.org/0000-0002-7233-5243Leeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United KingdomAstbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United Kingdom; School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, United KingdomInstitute of Biophotonics, National Yang-Ming University, Taipei, TaiwanLeeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United KingdomAstbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United Kingdom; School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, United KingdomInstitute of Biophotonics, National Yang-Ming University, Taipei, TaiwanAstbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United Kingdom; School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, United KingdomSchool of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United KingdomLeeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United KingdomLeeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United KingdomLeeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United KingdomLeeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United KingdomLeeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United KingdomLeeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United KingdomAstbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United Kingdom; School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds, United KingdomAstbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United Kingdom; School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds, United KingdomAstbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United Kingdom; School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds, United KingdomAstbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United Kingdom; School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Woodhouse Lane, Leeds, United KingdomSchool of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United KingdomInstitute of Biophotonics, National Yang-Ming University, Taipei, TaiwanAstbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United Kingdom; School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, United KingdomLeeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James’ University Hospital, Leeds, United Kingdom; Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United KingdomSince the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or ‘viroporins’, contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery. We describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery.https://elifesciences.org/articles/52555hepatitis c virusp7viroporinantiviral drugsvirion egressvirus entry |