Molecular mechanism of ensitrelvir inhibiting SARS-CoV-2 main protease and its variants.

Autor: Lin M; College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China.; Institute of Life Sciences, Chongqing Medical University, Chongqing, China.; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Zeng X; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Duan Y; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Yang Z; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Ma Y; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Yang H; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China., Yang X; Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai, China. yangxn@shanghaitech.edu.cn., Liu X; College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China. liux@nankai.edu.cn.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2023 Jul 05; Vol. 6 (1), pp. 694. Date of Electronic Publication: 2023 Jul 05.
DOI: 10.1038/s42003-023-05071-y
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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