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

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)...

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Bibliographic Details
Published in:eLife 2020-11, Vol.9
Main Authors: 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 J, Macdonald, Andrew, Tarr, Alexander W, Fischer, Wolfgang B, Foster, Richard, Griffin, Stephen
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
antiviral drugs
Biochemistry and Chemical Biology
Biomarkers
Cell Line
Daclatasvir
Dogs
Drug Discovery
Genotype
Health aspects
Hepacivirus - drug effects
Hepacivirus - metabolism
Hepatitis C virus
High-Throughput Screening Assays
Humans
Microbiology and Infectious Disease
Models, Molecular
Protein Conformation
Sofosbuvir
Structure-Activity Relationship
Viral Proteins - antagonists & inhibitors
Viral Proteins - metabolism
virion egress
viroporin
virus entry
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.52555