TY - JOUR TI - Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy AU - Shaw, Joseph AU - Gosain, Rajendra AU - Kalita, Monoj Mon AU - Foster, Toshana L AU - Kankanala, Jayakanth AU - Mahato, D Ram AU - Abas, Sonia AU - King, Barnabas J AU - Scott, Claire AU - Brown, Emma AU - Bentham, Matthew J AU - Wetherill, Laura AU - Bloy, Abigail AU - Samson, Adel AU - Harris, Mark AU - Mankouri, Jamel AU - Rowlands, David J AU - Macdonald, Andrew AU - Tarr, Alexander W AU - Fischer, Wolfgang B AU - Foster, Richard AU - Griffin, Stephen A2 - Brinkmann, Melanie M A2 - Boudker, Olga A2 - Gerold, Gisa VL - 9 PY - 2020 DA - 2020/11/10 SP - e52555 C1 - eLife 2020;9:e52555 DO - 10.7554/eLife.52555 UR - https://doi.org/10.7554/eLife.52555 AB - Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or ‘viroporinsâ€? 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. KW - hepatitis c virus KW - p7 KW - viroporin KW - antiviral drugs KW - virion egress KW - virus entry JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER - 管家婆期期准免费资料精选