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.© 2020, Shaw et al.
About The Expert
Joseph Shaw
Rajendra Gosein
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 Rowlands
Andrew Macdonald
Alexander W Tarr
Wolfgang B Fischer
Richard Foster
Stephen Griffin
References
PubMed