Publication date: Jul 16, 2026
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 Ms 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 Ms. In cellulo, AVI8122 efficiently inhibited the replication of SARS-CoV-2 and its variants of concern as well as the activity of Ms 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.
| Concepts | Keywords |
|---|---|
| Antivirals | |
| Avi8122 | |
| Broad | |
| Coronaviral | |
| Coronaviruses | |
| Cov | |
| Covalent | |
| Genera | |
| Inhibitor | |
| Main | |
| Pan | |
| Potent | |
| Sars | |
| Spectrum | |
| Structural |
Semantics
| Type | Source | Name |
|---|---|---|
| drug | DRUGBANK | L-Cysteine |
| disease | MESH | SARS-CoV-2 infection |
| pathway | REACTOME | SARS-CoV-2 Infection |