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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.<\/jats:p>","DOI":"10.7554\/elife.52555","type":"journal-article","created":{"date-parts":[[2020,11,10]],"date-time":"2020-11-10T08:00:37Z","timestamp":1604995237000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.52555","source":"Crossref","is-referenced-by-count":13,"title":["Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy"],"prefix":"10.7554","volume":"9","author":[{"given":"Joseph","family":"Shaw","sequence":"first","affiliation":[{"name":"Leeds Institute of Medical Research, School of Medicine, Faculty of Medicine and Health, University of Leeds, St James\u2019 University Hospital, Leeds, United Kingdom"},{"name":"Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, United 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