Publication: Functional and structural characterization of treatment-emergent nirmatrelvir resistance mutations at low frequencies in the main protease (Mpro) reveals a unique evolutionary route for SARS-CoV-2 to gain resistance

Summary: To treat COVID-19, many patients take the antiviral drug nirmatrelvir-ritonavir (Paxlovid), which inhibits SARS-CoV-2 chymotrypsin-like protease (M^pro/3CL^pro), an enzyme involved in virus replication. In this study, the authors analyzed 1,528 samples from patients treated with nirmatrelvir-ritonavir and identified antiviral resistance mutations in M^pro that occurred far from the catalytic site, leaving the protease activity intact while still conferring resistance to the antiviral drug. As these mutations were not identified in cell culture-based studies, this work highlights the importance of integrating clinical data into investigations of antiviral resistance.