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

Shaw, Joseph; Gosain, Rajendra; Kalita, Monoj Mon; Foster, Toshana L; Kankanala, Jayakanth; Mahato, D. Ram; Abas, Sonia; King, Barnabas J; Scott, Claire; Brown, Emma; Bentham, Matthew J; Wetherill, Laura; Bloy, Abigail; Samson, Adel; Harris, Mark; Mankouri, Jamel; Rowlands, David; Macdonald, Andrew; Tarr, Alexander W.; Fischer, Wolfgang B; Foster, Richard; Griffin, Stephen

Abstract

© 2020, Shaw et al. 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.

Citation

Shaw, J., Gosain, R., Kalita, M. M., Foster, T. L., Kankanala, J., Mahato, D. R., Abas, S., King, B. J., Scott, C., Brown, E., Bentham, M. J., Wetherill, L., Bloy, A., Samson, A., Harris, M., Mankouri, J., Rowlands, D., Macdonald, A., Tarr, A. W., Fischer, W. B., …Griffin, S. (2020). Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy. eLife, 9, Article e52555. https://doi.org/10.7554/eLife.52555

• Journal Article Type: Article
• Acceptance Date: Nov 9, 2020
• Online Publication Date: Dec 3, 2020
• Publication Date: Nov 10, 2020
• Deposit Date: Nov 11, 2020
• Publicly Available Date: Nov 13, 2020
• Journal: eLife
• Electronic ISSN: 2050-084X
• Publisher: eLife Sciences Publications
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Article Number: e52555
• DOI: https://doi.org/10.7554/eLife.52555
• Keywords: General Biochemistry, Genetics and Molecular Biology; General Immunology and Microbiology; General Neuroscience; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/5035676
• Publisher URL: https://elifesciences.org/articles/52555