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

• Main Authors: 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
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2020-11-01
• Series: eLife
• Subjects: hepatitis c virus; p7; viroporin; antiviral drugs; virion egress; virus entry
• Online Access: https://elifesciences.org/articles/52555

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.