biostudies-literatureBrown EUniversity of LeedsMedical Research CouncilUK Research and Innovatione68404https://www.ebi.ac.uk/biostudies/studies/S-EPMC11449487biostudies-literatureUnknown13<i>Flaviviruses</i>, including <i>Zika virus</i> (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 <i>trans</i>-membrane domain protomers were shown to comprise more stable assemblages than othereLifeInhibitors of the small membrane (M) protein viroporin prevent Zika virus infection.PMC11449487G0700124Impact Acceleration Account ( IAA)LIMR StudentshipMR/T016205/1MC_UU_12014/8Impact Acceleration Account (IAA)MR/N017552/1Lefteri DAKohl AMoran ABrown EBeaumont HKalli ACMaskell DThompson RFMcKimmie CSBentham MJSwinscoe GMacdonald AGriffin SSingh RDonald CRanson NFoster RfalseInhibitors of the small membrane (M) protein viroporin prevent Zika virus infection.<i>Flaviviruses</i>, including <i>Zika virus</i> (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 <i>trans</i>-membrane domain protomers were shown to comprise more stable assemblages than other2024-01-01T00:00:00Z2024 Aug2026-06-02T18:40:25.872Z2025-04-06T22:28:46.92ZS-EPMC114494873917730710.7554/eLife.68404