An ascidian Polycarpa aurata-derived pan-inhibitor against coronaviruses targeting M.

Coronaviruses (CoVs) are responsible for a wide range of illnesses in both animals and human. The main protease (M) of CoVs is an attractive drug target, owing its critical and highly conserved role in viral replication. Here, we developed and refined an enzymatic technique to identify putative M inhibitors from 189 marine chemicals and 46 terrestrial natural products. The IC values of Polycarpine (1a), a marine natural substance we studied and synthesized, are 30.0 ± 2.5 nM for SARS-CoV-2 M and 0.12 ± 0.05 μM for PEDV M. Our research further demonstrated that pretreatment with Polycarpine (1a) inhibited the betacoronavirus SARS-CoV-2 and alphacoronavirus PEDV multiplication in Vero-E6 cells. As a result, Polycarpine (1a), a pan-inhibitor of M, will function as an effective and promising antiviral option to combat CoVs infection and as a foundation for further therapeutic research.