Abstract

Flaviviruses, including Zika virus (ZIKV), are a significant global health concern, yet no licensed antivirals exist to treat disease. The small Membrane (M) protein plays well-defined roles during viral egress and remains within virion membranes following release and maturation. However, it is unclear whether M plays a functional role in this setting. Here, we show that M forms oligomeric membrane-permeabilising channels in vitro, with increased activity at acidic pH and sensitivity to the prototypic channel-blocker, rimantadine. Accordingly, rimantadine blocked an early stage of ZIKV cell culture infection. Structure-based channel models, comprising hexameric arrangements of two trans-membrane domain protomers were shown to comprise more stable assemblages than other oligomers using molecular dynamics (MD) simulations. Models contained a predicted lumenal rimantadine binding site, as well as a second druggable target region on the membrane-exposed periphery. In silico screening enriched for repurposed drugs/compounds predicted to bind to either one site or the other. Hits displayed superior potency in vitro and in cell culture compared with rimantadine, with efficacy demonstrably linked to virion-resident channels. Finally, rimantadine effectively blocked ZIKV viraemia in preclinical models, supporting that M constitutes a physiologically relevant target. This could be explored by repurposing rimantadine, or development of new M-targeted-therapies.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files; access to MD data and molecular models may be requested and, if accepted, accessed via MTA. Raw simulation data can be accessed via the Leeds Data Repository (https://archive.researchdata.leeds.ac.uk/) at the following DOI: https://doi.org/10.5518/1505

The following data sets were generated

Article and author information

Author details

  1. Emma Brown

    Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Gemma Swinscoe

    School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Daniella A Lefteri

    Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9985-4254
  4. Ravi Singh

    School of Chemistry, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4344-4085
  5. Amy Moran

    Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Rebecca F Thompson

    Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel Maskell

    School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Hannah Beaumont

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

    Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Claire Donald

    Institute of infection, immunity and inflammation, MRC University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Alain Kohl

    Institute of infection, immunity and inflammation, MRC University of Glasgow Centre for Virus Research, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Andrew Macdonald

    Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Neil A Ranson

    Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Richard Foster

    School of Chemistry, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Clive S McKimmie

    Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Antreas C Kalli

    Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7156-9403
  17. Stephen Griffin

    Leeds Institute of Medical Research, 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
  • Stephen Griffin

University of Leeds (LIMR Studentship)

  • Emma Brown
  • Richard Foster
  • Clive S McKimmie
  • Antreas C Kalli
  • Stephen Griffin

Medical Research Council (MC_UU_12014/8)

  • Claire Donald
  • Alain Kohl

Medical Research Council (MR/N017552/1)

  • Claire Donald
  • Alain Kohl

University of Leeds (LIMR Studentship)

  • Daniella A Lefteri
  • Clive S McKimmie
  • Stephen Griffin

Medical Research Council (MR/T016205/1)

  • Amy Moran
  • Stephen Griffin

UK Research and Innovation (Impact Acceleration Account ( IAA))

  • Gemma Swinscoe

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

Ethics

Animal experimentation: Procedures were carried out in accordance with the United Kingdom Home Office regulations under the authority of the appropriate project and personal license (awarded to CSM, and CSM/DL respectively).

Copyright

© 2024, Brown 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. Emma Brown
  2. Gemma Swinscoe
  3. Daniella A Lefteri
  4. Ravi Singh
  5. Amy Moran
  6. Rebecca F Thompson
  7. Daniel Maskell
  8. Hannah Beaumont
  9. Matthew J Bentham
  10. Claire Donald
  11. Alain Kohl
  12. Andrew Macdonald
  13. Neil A Ranson
  14. Richard Foster
  15. Clive S McKimmie
  16. Antreas C Kalli
  17. Stephen Griffin
(2024)
Inhibitors of the small membrane (M) protein viroporin prevent Zika virus infection
eLife 13:e68404.
https://doi.org/10.7554/eLife.68404

Share this article

https://doi.org/10.7554/eLife.68404

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