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)

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 > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
		Viral Genomics and Bioinformatics	Andrew Davison	Medical Research Council (MRC)	MC_UU_12014/12	III-MRC-GU Centre for Virus Research