RT Journal Article
SR Electronic
T1 Inhibitors of the Small Membrane (M) Protein Viroporin Prevent Zika Virus Infection
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.11.435022
DO 10.1101/2021.03.11.435022
A1 Emma Brown
A1 Daniella Lefteri
A1 Ravi Singh
A1 Rebecca Thompson
A1 Daniel Maskell
A1 Hannah Beaumont
A1 Matthew Bentham
A1 Gemma Swinscoe
A1 Andres Merits
A1 Claire Donald
A1 Alain Kohl
A1 Andrew Macdonald
A1 Neil Ranson
A1 Richard Foster
A1 Clive S. McKimmie
A1 Antreas C. Kalli
A1 Stephen Griffin
YR 2021
UL http://biorxiv.org/content/early/2021/03/12/2021.03.11.435022.abstract
AB Flaviviruses, including Zika virus (ZIKV), are a significant global health concern, yet no licensed antivirals exist to treat disease. The small M (Membrane) protein plays well-defined roles during viral egress, yet 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. In turn, rimantadine blocked an early stage of ZIKV cell culture infection.Molecular dynamics (MD) generated rationalised structure-based channel models, comprising hexameric arrangements of dual trans-membrane protomers. Interestingly, His28 protonation increased channel opening, consistent with activation within acidifying endosomes. Models contained a predicted lumenal binding site for rimantadine, as well as a second target region on the membrane-exposed periphery. In silico screening enriched for repurposed drugs/compounds predicted to bind to one or other site. Multiple hits displayed potency in vitro and in cell culture, supporting the relevance of channel models. Finally, rimantadine effectively blocked ZIKV viraemia in a preclinical model, supporting that M constitutes a physiologically relevant antiviral target, for either repurposing rimantadine, or the development of new ZIKV therapies.Competing Interest StatementThe authors have declared no competing interest.