tetano
Editor, Senior Moderator
J Med Chem
. 2026 Jul 16.
doi: 10.1021/acs.jmedchem.6c00645. Online ahead of print.
Identification of a Potent Pan-Coronaviral Main Protease Inhibitor
Pu Chen[SUP] 1 2 [/SUP], Ulrike Strunk[SUP] 2 3 [/SUP], Elena Arutyunova[SUP] 1 2 [/SUP], Jimmy Lu[SUP] 1 2 [/SUP], Sizhu Amelia Chen[SUP] 1 2 [/SUP], Sydney Demmon[SUP] 1 2 [/SUP], Cassidy Maplethorpe[SUP] 1 2 [/SUP], Appan Srinivas Kandadai[SUP] 3 4 [/SUP], Justin Shields[SUP] 2 3 [/SUP], Holly A Saffran[SUP] 2 3 [/SUP], Tess Lamer[SUP] 5 [/SUP], Conrad Fischer[SUP] 5 [/SUP], Tayla J Van Oers[SUP] 5 [/SUP], Zoe Turner[SUP] 1 2 [/SUP], Parco Leong[SUP] 1 2 [/SUP], Jegan Iyyathurai[SUP] 1 2 [/SUP], Howard S Young[SUP] 1 [/SUP], Bing Bai[SUP] 3 4 [/SUP], John C Vederas[SUP] 5 [/SUP], James A Nieman[SUP] 3 4 [/SUP], Michael A Joyce[SUP] 2 3 [/SUP], D Lorne Tyrrell[SUP] 2 3 [/SUP], M Joanne Lemieux[SUP] 1 2 [/SUP]
Affiliations
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[SUP]pro[/SUP]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[SUP]pro[/SUP]s. In cellulo, AVI8122 efficiently inhibited the replication of SARS-CoV-2 and its variants of concern as well as the activity of M[SUP]pro[/SUP]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.
. 2026 Jul 16.
doi: 10.1021/acs.jmedchem.6c00645. Online ahead of print.
Identification of a Potent Pan-Coronaviral Main Protease Inhibitor
Pu Chen[SUP] 1 2 [/SUP], Ulrike Strunk[SUP] 2 3 [/SUP], Elena Arutyunova[SUP] 1 2 [/SUP], Jimmy Lu[SUP] 1 2 [/SUP], Sizhu Amelia Chen[SUP] 1 2 [/SUP], Sydney Demmon[SUP] 1 2 [/SUP], Cassidy Maplethorpe[SUP] 1 2 [/SUP], Appan Srinivas Kandadai[SUP] 3 4 [/SUP], Justin Shields[SUP] 2 3 [/SUP], Holly A Saffran[SUP] 2 3 [/SUP], Tess Lamer[SUP] 5 [/SUP], Conrad Fischer[SUP] 5 [/SUP], Tayla J Van Oers[SUP] 5 [/SUP], Zoe Turner[SUP] 1 2 [/SUP], Parco Leong[SUP] 1 2 [/SUP], Jegan Iyyathurai[SUP] 1 2 [/SUP], Howard S Young[SUP] 1 [/SUP], Bing Bai[SUP] 3 4 [/SUP], John C Vederas[SUP] 5 [/SUP], James A Nieman[SUP] 3 4 [/SUP], Michael A Joyce[SUP] 2 3 [/SUP], D Lorne Tyrrell[SUP] 2 3 [/SUP], M Joanne Lemieux[SUP] 1 2 [/SUP]
Affiliations
- PMID: 42461134
- DOI: 10.1021/acs.jmedchem.6c00645
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[SUP]pro[/SUP]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[SUP]pro[/SUP]s. In cellulo, AVI8122 efficiently inhibited the replication of SARS-CoV-2 and its variants of concern as well as the activity of M[SUP]pro[/SUP]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.