Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion release

Foster, T. L. et al. (2014) Structure-guided design affirms inhibitors of hepatitis C virus p7 as a viable class of antivirals targeting virion release. Hepatology, 59(2), pp. 408-422. (doi: 10.1002/hep.26685) (PMID:24022996) (PMCID:PMC4298801)

Abstract

Current interferon‐based therapy for hepatitis C virus (HCV) infection is inadequate, prompting a shift toward combinations of direct‐acting antivirals (DAA) with the first protease‐targeted drugs licensed in 2012. Many compounds are in the pipeline yet primarily target only three viral proteins, namely, NS3/4A protease, NS5B polymerase, and NS5A. With concerns growing over resistance, broadening the repertoire for DAA targets is a major priority. Here we describe the complete structure of the HCV p7 protein as a monomeric hairpin, solved using a novel combination of chemical shift and nuclear Overhauser effect (NOE)‐based methods. This represents atomic resolution information for a full‐length virus‐coded ion channel, or “viroporin,” whose essential functions represent a clinically proven class of antiviral target exploited previously for influenza A virus therapy. Specific drug‐protein interactions validate an allosteric site on the channel periphery and its relevance is demonstrated by the selection of novel, structurally diverse inhibitory small molecules with nanomolar potency in culture. Hit compounds represent a 10,000‐fold improvement over prototypes, suppress rimantadine resistance polymorphisms at submicromolar concentrations, and show activity against other HCV genotypes. Conclusion: This proof‐of‐principle that structure‐guided design can lead to drug‐like molecules affirms p7 as a much‐needed new target in the burgeoning era of HCV DAA.

• Item Type: Articles
• Additional Information: TLF was supported by a Wellcome Trust PhD studentship (to MH and ARP) and subsequently by a Yorkshire Cancer Research Award (SG, PP025). Work in the Griffin laboratory was also supported by the University of Leeds Biomedical Health Research Centre (BHRC), the Leeds CRUK clinical centre, a UK Royal Society project award (SG, RG081138), and a Medical Research Council New Investigator Research Grant (SG, G0700124). MH is the recipient of a Wellcome Trust Investigator Award and SG holds a Senior Fellowship with the University of Leeds BHRC.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Noerenberg, Dr Marko
• Authors: Foster, T. L., Thompson, G. S., Kalverda, A. P., Kankanala, J., Bentham, M., Wetherill, L. F., Thompson, J., Barker, A. M., Clarke, D., Noerenberg, M., Pearson, A. R., Rowlands, D. J., Homans, S. W., Harris, M., Foster, R., and Griffin, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Hepatology
• Publisher: Wiley
• ISSN: 0270-9139
• ISSN (Online): 1527-3350
• Published Online: 12 August 2013
• Copyright Holders: Copyright © 2013 The Authors
• First Published: First published in Hepatology 59(2): 408-422
• Publisher Policy: Reproduced under a Creative Commons License