Faculty of Science
Microbiology and Immunology

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

Schematic of protein-drug interactions

Publication Date

Publication Journal

The Journal of Infectious Diseases

Author(s)

Natalie M. Deschenes, Jimena Pérez-Vargas, Zoe Zhong,3 Merrilee Thomas, Calem Kenward, Wesley A. Mosimann, Liam J. Worrall, Nicholas Waglechner, Angel Xin Liu Li, Finlay Maguire, Patryk Aftanas, Jason R. Smith, Jared Lim, Robert N. Young, Artem Cherkasov, Lubna Farooqi, Adnan Moinuddin, Lina Siddiqi, Imaan Malik, Maxime Lefebvre, Mark Paetzel, Natalie C. J. Strynadka, François Jean, Allison McGeer,and Robert A. Kozak

To treat COVID-19, many patients take the antiviral drug nirmatrelvir-ritonavir (PaxlovidÔ), which inhibits SARS-CoV-2 chymotrypsin-like protease (Mpro/3CLpro), 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 Mpro 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.

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Microbiology and Immunology

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