Crystal structures of main protease (M pro ) mutants of SARS-CoV-2 variants bound to PF-07304814.
Jiang, H., Zou, X., Zeng, P., Zeng, X., Zhou, X., Wang, J., Zhang, J., Li, J.(2023) Mol Biomed 4: 23-23
- PubMed: 37532968
- DOI: https://doi.org/10.1186/s43556-023-00134-2
- Primary Citation of Related Structures:
8HVU, 8HVV, 8HVW, 8HVX, 8HVY, 8HVZ - PubMed Abstract:
There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease (M pro ) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 M pro with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 M pro . However, the binding modes of PF-07304814 with M pro s from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six M pro mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to M pro mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant M pro s. Patterns for PF-07304814 to bind with these investigated M pro mutants and the wild-type M pro are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of M pro mutants when bound to an inhibitor.
Organizational Affiliation:
School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, China.