Coronavirus resistance to papain-like protease inhibitors

All known coronaviruses encode a conserved papain-like protease (PLpro) that is essential for viral replication and has been an attrative but challenging target for antiviral development. Recent studies have reported PLpro inhibitors exhibiting in vivo efficacy and oral bioavailability to inhibit SARS-CoV-2 infection in mice models, providing oral drug candidates for further development. One critical aspect of the development is to analyzeviral resistance to the inhibitors. The goal of this study is to identify mutations that confer resistance to PLpro inhibitors.