Download MendeleyMolecular mechanism of ensitrelvir inhibiting SARS-CoV-2 main protease and its variants.
Lin, M., Zeng, X., Duan, Y., Yang, Z., Ma, Y., Yang, H., Yang, X., Liu, X.(2023) Commun Biol 6: 694-694
- PubMed: 37407698
- DOI: https://doi.org/10.1038/s42003-023-05071-y
- Primary Citation of Related Structures:
8HOL, 8HOM, 8HOZ, 8INQ, 8INT, 8INU, 8INW, 8INX, 8INY - PubMed Abstract:
SARS-CoV-2 poses an unprecedented threat to the world as the causative agent of the COVID-19 pandemic. Among a handful of therapeutics developed for the prevention and treatment of SARS-CoV-2 infection, ensitrelvir is the first noncovalent and nonpeptide oral inhibitor targeting the main protease (M pro ) of SARS-CoV-2, which recently received emergency regulatory approval in Japan. Here we determined a 1.8-Å structure of M pro in complex with ensitrelvir, which revealed that ensitrelvir targets the substrate-binding pocket of M pro , specifically recognizing its S1, S2, and S1' subsites. Further, our comprehensive biochemical and structural data have demonstrated that even though ensitrelvir and nirmatrelvir (an FDA-approved drug) belong to different types of M pro inhibitors, both of them remain to be effective against M pro s from all five SARS-CoV-2 variants of concern, suggesting M pro is a bona fide broad-spectrum target. The molecular mechanisms uncovered in this study provide basis for future inhibitor design.
Organizational Affiliation:
College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.
