Inhibitors of the small membrane (M) protein viroporin prevent Zika virus infection

• DOI: 10.7554/elife.68404
• Publication Date: 2024-08-23T09:15:21Z
• Authors: Emma Brown; Gemma Swinscoe; Daniella A Lefteri; Ravi Singh; Amy Moran; Rebecca F Thompson; Daniel Maskell; Hannah Beaumont; Matthew J Bentham; Claire Donald; Alain Kohl; Andrew Macdonald; Neil Ranson; Richard Foster; Clive S McKimmie; Antreas C Kalli; Stephen Griffin
• Keywords: Rimantadine; Druggability; Repurposing; Zika Virus; Viral membrane

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 maturation. However, it is unclear whether M functional role in this setting. Here, we show that forms oligomeric membrane-permeabilising channels vitro, with increased activity at acidic pH sensitivity the prototypic channel-blocker, rimantadine. Accordingly, rimantadine blocked an early stage of ZIKV cell culture infection. Structure-based channel models, comprising hexameric arrangements two trans -membrane domain protomers were shown comprise more stable assemblages than other oligomers using molecular dynamics simulations. Models contained predicted lumenal rimantadine-binding site, as well second druggable target region on membrane-exposed periphery. In silico screening enriched for repurposed drugs/compounds bind either one site or other. Hits displayed superior potency vitro compared rimantadine, efficacy demonstrably linked virion-resident channels. Finally, effectively viraemia preclinical supporting constitutes physiologically relevant target. This could be explored by repurposing development new M-targeted therapies.