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

Abstract

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures.

Article and author information

Author details

  1. Joseph Shaw

    Leeds Institute of Medical Research, School of Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Rajendra Gosein

    School of Chemistry, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Monoj Mon Kalita

    Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8037-8489
  4. Toshana L Foster

    School of Chemistry, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Jayakanth Kankanala

    School of Chemistry, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. D Ram Mahato

    Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
  7. Sonia Abas

    School of Chemistry, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Barnabas J King

    School of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8432-2282
  9. Claire Scott

    School of Chemistry, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Emma Brown

    Leeds Institute of Medical Research, School of Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Matthew J Bentham

    School of Chemistry, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Laura Wetherill

    Leeds Institute of Medical Research, School of Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Abigail Bloy

    Leeds Institute of Medical Research, School of Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Adel Samson

    Leeds Institute of Medical Research, School of Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Mark Harris

    School of Chemistry, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Jamel Mankouri

    School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  17. David Rowlands

    School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  18. Andrew Macdonald

    School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  19. Alexander W Tarr

    School of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1009-0823
  20. Wolfgang B Fischer

    Institute of Biophotonics, National Yang-Ming University, Taipei, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
  21. Richard Foster

    School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
    For correspondence
    r.foster@leeds.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  22. Stephen Griffin

    Leeds Institute of Medical Research, School of Medicine, University of Leeds, Leeds, United Kingdom
    For correspondence
    s.d.c.griffin@leeds.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7233-5243

Funding

Medical Research Council (G0700124)

  • Matthew J Bentham
  • Laura Wetherill
  • Stephen Griffin

Yorkshire Cancer Research Pump-Priming Award (PP025)

  • Toshana L Foster
  • Stephen Griffin

Leeds Teaching Hospitals Charitable Foundation (9R11/14-03)

  • Laura Wetherill
  • Stephen Griffin

Medical Research Council (MC.PC.13066)

  • Joseph Shaw
  • Rajendra Gosein
  • Richard Foster
  • Stephen Griffin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Melanie M Brinkmann, Technische Universität Braunschweig, Germany

Publication history

  1. Received: October 8, 2019
  2. Accepted: November 9, 2020
  3. Accepted Manuscript published: November 10, 2020 (version 1)
  4. Accepted Manuscript updated: November 12, 2020 (version 2)
  5. Version of Record published: December 3, 2020 (version 3)
  6. Version of Record updated: December 3, 2020 (version 4)

Copyright

© 2020, Shaw et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Joseph Shaw
  2. Rajendra Gosein
  3. Monoj Mon Kalita
  4. Toshana L Foster
  5. Jayakanth Kankanala
  6. D Ram Mahato
  7. Sonia Abas
  8. Barnabas J King
  9. Claire Scott
  10. Emma Brown
  11. Matthew J Bentham
  12. Laura Wetherill
  13. Abigail Bloy
  14. Adel Samson
  15. Mark Harris
  16. Jamel Mankouri
  17. David Rowlands
  18. Andrew Macdonald
  19. Alexander W Tarr
  20. Wolfgang B Fischer
  21. Richard Foster
  22. Stephen Griffin
(2020)
Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy
eLife 9:e52555.
https://doi.org/10.7554/eLife.52555