Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease

by Noske GD, de Souza Silva E, de Godoy MO, Dolci I, Fernandes RS, Guido RVC, Sjö P, Oliva G, Godoy AS. Journal of Biological Chemistry 2023. doi: https://doi.org/10.1016/j.jbc.2023.103004

Summary: The main viral protease (M^pro) of SARS-CoV-2 is an attractive target for antivirals, including the clinically approved drug nirmatrelvir and the clinical candidate ensitrelvir. While these molecules have potential for the treatment of viral infection, if used broadly, there is the risk of resistance generation. To help predict the likelihood of resistance, the authors enzymatically characterized 14 naturally occurring M^pro polymorphisms. Nirmatrelvir and ensitrelvir appeared to have distinct resistance profiles, and the crystal structures of selected polymorphisms revealed interactions that were critical for loss of potency. This data will assist the monitoring of potential resistant strains, support the design of combined therapy, and support the development of the next generation of M^pro inhibitors.