Rationally derived inhibitors of hepatitis c virus (Hcv) p7 channel activity reveal prospect for bimodal antiviral therapy

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. FischerRichard Foster*, Stephen Griffin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Article numbere52555
Pages (from-to)1-36
Number of pages36
JournaleLife
Volume9
DOIs
StatePublished - Oct 2020

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