Inhibitors of the small membrane (M) protein viroporin prevent Zika virus infection
- University of Leeds, United Kingdom
- MRC University of Glasgow Centre for Virus Research, United Kingdom
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
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ZIKV M protein simulation dataLeeds Data Repository, 974.
Article and author information
Author details
Daniella A Lefteri
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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Inhibitors of the small membrane (M) protein viroporin prevent Zika virus infection
eLife 13:e68404.
https://doi.org/10.7554/eLife.68404
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