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Resistance mutations define specific antiviral effects for inhibitors of the hepatitis C virus p7 ion channel

Foster, Toshana L.; Verow, Mark; Wozniak, Ann L.; Bentham, Matthew J.; Thompson, Joseph; Atkins, Elizabeth; Weinman, Steven A.; Fishwick, Colin; Foster, Richard; Harris, Mark; Griffin, Stephen


Mark Verow

Ann L. Wozniak

Matthew J. Bentham

Joseph Thompson

Elizabeth Atkins

Steven A. Weinman

Colin Fishwick

Richard Foster

Mark Harris

Stephen Griffin


The hepatitis C virus (HCV) p7 ion channel plays a critical role during infectious virus production and represents an important new therapeutic target. Its activity is blocked by structurally distinct classes of small molecules, with sensitivity varying between isolate p7 sequences. Although this is indicative of specific protein–drug interactions, a lack of high‐resolution structural information has precluded the identification of inhibitor binding sites, and their modes of action remain undefined. Furthermore, a lack of clinical efficacy for existing p7 inhibitors has cast doubt over their specific antiviral effects. We identified specific resistance mutations that define the mode of action for two classes of p7 inhibitor: adamantanes and alkylated imino sugars (IS). Adamantane resistance was mediated by an L20F mutation, which has been documented in clinical trials. Molecular modeling revealed that L20 resided within a membrane‐exposed binding pocket, where drug binding prevented low pH‐mediated channel opening. The peripheral binding pocket was further validated by a panel of adamantane derivatives as well as a bespoke molecule designed to bind the region with high affinity. By contrast, an F25A polymorphism found in genotype 3a HCV conferred IS resistance and confirmed that these compounds intercalate between p7 protomers, preventing channel oligomerization. Neither resistance mutation significantly reduced viral fitness in culture, consistent with a low genetic barrier to resistance occurring in vivo. Furthermore, no cross‐resistance was observed for the mutant phenotypes, and the two inhibitor classes showed additive effects against wild‐type HCV. Conclusion: These observations support the notion that p7 inhibitor combinations could be a useful addition to future HCV‐specific therapies.


Foster, T. L., Verow, M., Wozniak, A. L., Bentham, M. J., Thompson, J., Atkins, E., …Griffin, S. (2011). Resistance mutations define specific antiviral effects for inhibitors of the hepatitis C virus p7 ion channel. Hepatology, 54(1), 79-90. doi:10.1002/hep.24371

Journal Article Type Article
Acceptance Date Apr 11, 2011
Online Publication Date Jun 24, 2011
Publication Date Jun 24, 2011
Deposit Date Mar 22, 2019
Journal Hepatology
Print ISSN 0270-9139
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 54
Issue 1
Pages 79-90
Keywords Hepatology
Public URL
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