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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

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Joseph Shaw

Rajendra Gosain

Monoj Mon Kalita

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

Wolfgang B Fischer

Richard Foster

Stephen Griffin


© 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.

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
Keywords General Biochemistry, Genetics and Molecular Biology; General Immunology and Microbiology; General Neuroscience; General Medicine
Public URL
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