Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures

Zafferani, M. et al. (2021) Amilorides inhibit SARS-CoV-2 replication in vitro by targeting RNA structures. Science Advances, 7(48), eabl6096. (doi: 10.1126/sciadv.abl6096) (PMID:34826236)

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Abstract

The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, emphasized the urgent need for development of novel antivirals. Small-molecule chemical probes offer both to reveal aspects of virus replication and to serve as leads for antiviral therapeutic development. Here, we report on the identification of amiloride-based small molecules that potently inhibit OC43 and SARS-CoV-2 replication through targeting of conserved structured elements within the viral 5′-end. Nuclear magnetic resonance–based structural studies revealed specific amiloride interactions with stem loops containing bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Amilorides represent the first antiviral small molecules that target RNA structures within the 5′ untranslated regions and proximal region of the CoV genomes. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA–targeted antivirals.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gifford, Dr Robert
Creator Roles:
Gifford, R. J.Conceptualization, Writing – review and editing
Authors: Zafferani, M., Haddad, C., Luo, L., Davila-Calderon, J., Chiu, L.-Y., Mugisha, C. S., Monaghan, A. G., Kennedy, A. A., Yesselman, J. D., Gifford, R. J., Tai, A. W., Kutluay, S. B., Li, M.-L., Brewer, G., Tolbert, B. S., and Hargrove, A. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Centre for Virus Research
Journal Name:Science Advances
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
ISSN (Online):2375-2548
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Science Advances 7(48): eabl6096
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
Viral Genomics and BioinformaticsAndrew DavisonMedical Research Council (MRC)MC_UU_12014/12III-MRC-GU Centre for Virus Research