McKimmie, Clive Stewart orcid.org/0000-0002-7694-9509 (2024) Inhibitors of the small membrane (M) protein viroporin prevent Zika virus infection. eLife. e68404. ISSN: 2050-084X
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 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © Brown et al. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Hull York Medical School (York) |
Depositing User: | Pure (York) |
Date Deposited: | 25 Sep 2025 10:30 |
Last Modified: | 25 Sep 2025 10:30 |
Published Version: | https://doi.org/10.7554/eLife.68404 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.7554/eLife.68404 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:232229 |