Identification of a Potent Pan-Coronaviral Main Protease Inhibitor
The global impact of SARS-CoV-2 and the continued emergence of zoonotic coronaviruses underscore the urgent need for broad-spectrum antivirals for pandemic preparedness. Herein, we report AVI8122, a covalent pan-coronaviral inhibitor that targets 19 M pro s across the α, β, γ, and δ genera, encompassing bat, human, and other animal coronaviruses. AVI8122 exhibits low nanomolar potency and favorable pharmacokinetics in mice. Structural studies reveal that AVI8122 forms a covalent bond with the catalytic cysteine and maintains conserved interactions within the active sites of these M pro s. In cellulo, AVI8122 efficiently inhibited the replication of SARS-CoV-2 and its variants of concern as well as the activity of M pro s from all four genera. Furthermore, in mouse models, AVI8122 conferred dose-dependent protection against a lethal SARS-CoV-2 infection. Our findings position AVI8122 as an early lead compound and a tractable structural starting point for the development of broad-spectrum antivirals against future coronavirus spillover threats.
Authors
- Jegan Iyyathurai
- Michael Joyce (ORCID: https://orcid.org/0000-0002-9173-7299)
- John C. Vederas (ORCID: https://orcid.org/0000-0002-2996-0326)
- Elena Arutyunova (ORCID: https://orcid.org/0000-0003-4119-3622)
- Howard S. Young (ORCID: https://orcid.org/0000-0002-5990-8422)
- Tess Lamer (ORCID: https://orcid.org/0000-0002-1511-4540)
- Holly A. Saffran
- P.S. Chen (ORCID: https://orcid.org/0000-0002-0434-6346)
- Jimmy Lu (ORCID: https://orcid.org/0000-0002-4090-5176)
- Zoe Turner (ORCID: https://orcid.org/0000-0002-3130-5208)
- Sizhu Amelia Chen (ORCID: https://orcid.org/0000-0003-2412-2697)
- Conrad Fischer (ORCID: https://orcid.org/0000-0002-2289-010X)
- Ulrike Strunk
- D TYRRELL
- James A. Nieman (ORCID: https://orcid.org/0000-0002-5087-0819)
- Tayla J. Van Oers (ORCID: https://orcid.org/0009-0006-2314-560X)
- Bing Bai (ORCID: https://orcid.org/0000-0003-4102-305X)
- Appan Srinivas Kandadai
- Sydney Demmon
- M Joanne Lemieux (ORCID: https://orcid.org/0000-0003-4745-9153)
- Justin Shields (ORCID: https://orcid.org/0000-0003-4701-4576)
- Cassidy Maplethorpe
- Parco Leong
Institutions
- University of Alberta (CA)
- Institute of Virology of the Slovak Academy of Sciences (SK)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-07-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00645
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- GlaxoSmithKline
- Government of Alberta
- Canada Foundation for Innovation
- Li Ka Shing Institute of Virology, University of Alberta