Research Data Leeds Repository

Citation

Brown, Emma and Kalli, Antreas and Griffin, Stephen (2024) Inhibitors of the Small Membrane (M) Protein Viroporin Prevent Zika Virus Infection - dataset. University of Leeds. [Dataset] https://doi.org/10.5518/1505

Dataset description

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 (MD) 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.

Keywords:	Zika virus, ion channel, M protein
Subjects:	C000 - Biological sciences > C700 - Molecular biology, biophysics & biochemistry
Divisions:	Faculty of Medicine and Health > School of Medicine
Related resources:	Location Type https://doi.org/10.7554/elife.68404 Publication https://eprints.whiterose.ac.uk/216705/ Publication
License:	Creative Commons Attribution 4.0 International (CC BY 4.0)
Date deposited:	30 Sep 2024 20:05
URI:	https://archive.researchdata.leeds.ac.uk/id/eprint/1325
Additional details Additional details Creators or authors: Creators ORCID Other ID Email Primary affiliation Primary affiliation ID Primary affiliation ID type Secondary affiliation Secondary affiliation ID Secondary affiliation ID type Brown, Emma University of Leeds https://ror.org/024mrxd33 ror Kalli, Antreas https://orcid.org/0000-0001-7156-9403 University of Leeds https://ror.org/024mrxd33 ror Griffin, Stephen https://orcid.org/0000-0002-7233-5243 University of Leeds https://ror.org/024mrxd33 ror Type of data: Dataset Research funders: Institute PhD Scholarships from the Leeds Institute of Medical Research, University of Leeds, MRC Grant numbers: N/A, G0700124, MC_UU_12014/8 Publication date: 2024 Resource language: English Metadata language: English Publisher: University of Leeds Contact email: a.kalli@leeds.ac.uk Last Modified: 01 Oct 2024 10:30

Files

Documentation

Simulation_data_M_protein.zip [11GB] Simulation_data_M_protein.zip [11GB] Simulation_data_M_protein.zip [11GB] Security: Anyone File name: Simulation_data_M_protein.zip Content type: Documentation Mime-Type: application/zip License: Creative Commons Attribution 4.0 International (CC BY 4.0) File size: 11GB

Data

README_Kalli_2024.txt [12kB] README_Kalli_2024.txt [12kB] README_Kalli_2024.txt [12kB] Security: Anyone File name: README_Kalli_2024.txt Content type: Data Mime-Type: text/plain License: Creative Commons Attribution 4.0 International (CC BY 4.0) File size: 12kB