Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy
- University of Leeds, United Kingdom
- National Yang-Ming University, Taiwan
- University of Nottingham, United Kingdom
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures.
Article and author information
Author details
Funding
Medical Research Council (G0700124)
- Matthew J Bentham
- Laura Wetherill
- Stephen Griffin
Yorkshire Cancer Research Pump-Priming Award (PP025)
- Toshana L Foster
- Stephen Griffin
Leeds Teaching Hospitals Charitable Foundation (9R11/14-03)
- Laura Wetherill
- Stephen Griffin
Medical Research Council (MC.PC.13066)
- Joseph Shaw
- Rajendra Gosein
- Richard Foster
- Stephen Griffin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Melanie M Brinkmann, Technische Universität Braunschweig, Germany
Version history
- Received: October 8, 2019
- Accepted: November 9, 2020
- Accepted Manuscript published: November 10, 2020 (version 1)
- Accepted Manuscript updated: November 12, 2020 (version 2)
- Version of Record published: December 3, 2020 (version 3)
- Version of Record updated: December 3, 2020 (version 4)
Copyright
© 2020, Shaw et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy
eLife 9:e52555.
https://doi.org/10.7554/eLife.52555
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