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

作者全名："Lin, Mengmeng; Zeng, Xudong; Duan, Yinkai; Yang, Zinan; Ma, Yuanyuan; Yang, Haitao; Yang, Xiuna; Liu, Xiang"

作者地址："[Lin, Mengmeng; Liu, Xiang] Nankai Univ, Coll Life Sci, State Key Lab Med Chem Biol, Tianjin, Peoples R China; [Lin, Mengmeng] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Lin, Mengmeng; Zeng, Xudong; Duan, Yinkai; Yang, Zinan; Ma, Yuanyuan; Yang, Haitao; Yang, Xiuna] ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China; [Lin, Mengmeng; Zeng, Xudong; Duan, Yinkai; Yang, Zinan; Ma, Yuanyuan; Yang, Haitao; Yang, Xiuna] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China"

通信作者："Liu, X (通讯作者)，Nankai Univ, Coll Life Sci, State Key Lab Med Chem Biol, Tianjin, Peoples R China.; Yang, XA (通讯作者)，ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China.; Yang, XA (通讯作者)，ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China."

来源：COMMUNICATIONS BIOLOGY

ESI学科分类：　

WOS号：WOS:001024010100001

JCR分区：Q1

影响因子：5.9

年份：2023

卷号：6

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："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-& ANGS; 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. Structural and biochemical characterization of the SARS-CoV-2 main protease in complex with inhibitor ensitrelvir or nirmatrelvir reveals the mechanisms of inhibition."

基金机构："Ramp;D Program of Guangzhou Laboratory [SRPG22-003, SRPG22-011]; Science and Technology Commission of Shanghai Municipality [YDZX20213100001556, 20XD1422900]; Shanghai Municipal Science and Technology Major Project [ZD2021CY001]; National Natural Science Foundation of China [92169109, 32171259]; Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine, Shanghai Tech University"

基金资助正文："This work was supported by grants from the R & D Program of Guangzhou Laboratory (grant No. SRPG22-003 and SRPG22-011); Science and Technology Commission of Shanghai Municipality (grant No. YDZX20213100001556 and 20XD1422900 to H.Y.); Shanghai Municipal Science and Technology Major Project (grant No. ZD2021CY001); National Natural Science Foundation of China (grant No. 92169109 to H.Y. and grant No. 32171259 to X.L.) This work was supported by Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine, Shanghai Tech University. We would like to acknowledge the staff members from beamlines BL02U1, BL10U2, BL18U1, and BL19U1 at the Shanghai Synchrotron Radiation Facility and I04 beamline of Diamond Light Source for the beam time and operation at the facility."