The Flavivirus small integral membrane (M) protein resides within mature infectious particles yet, unlike the envelope (E) protein which mediates membrane fusion upon encountering low pH within the acidifying endosome, the function of M within this context is unknown. We are investigating whether Zika virus (ZIKV) M protein exhibits channel activity, acting as a viroporin playing a role mediating virus entry and uncoating. Importantly, ZIKV entry was blocked in a dose-dependent fashion by the prototypic channel blocker rimantadine and the drug also prevented virus spread in mouse models of ZIKV infection. Molecular dynamics simulations supported that M protein is able to oligomerise into a hexameric viroporin channel, opening of which is promoted in an acidified environment via protonation of a conserved histidine residue. Rimantadine is predicted to bind onto this structure in silico at a lumenal binding site, against which we are currently designing improved small molecule inhibitors that could form the basis of novel M protein targeted drug discovery. Importantly, drugs targeting M might either prevent or reduce the severity of ZIKV infections, including those crossing the placenta, and could also be translated for use against other Flaviviruses.

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