Crystal structures of main proteases of SARS-CoV-2 variants bound to a benzothiazole-based inhibitor  

作　　者：Jiqing Luo Weiwei Wang Haihai Jiang Wenwen Li Pei Zeng Jie Wang Xuelan Zhou Xiaofang Zou Shenghui Chen Qisheng Wang Jin Zhang Jian Li 

机构地区：[1]College of Pharmaceutical Sciences,Gannan Medical University,Ganzhou 341000,China [2]Shanghai Advanced Research Institute,Chinese Academy of Sciences,Shanghai 201204,China [3]School of Basic Medical Sciences,Nanchang University,Nanchang 330031,China [4]Shenzhen Crystalo Biopharmaceutical Co.,Ltd.,Shenzhen 518118,China [5]Jiangxi Jmerry Biopharmaceutical Co.,Ltd.,Ganzhou 341000,China [6]Nanchang Reproductive Hospital,Nanchang 330000,China

出　　处：《Acta Biochimica et Biophysica Sinica》2023年第8期1257-1264,共8页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the Gannan Medical University(No.QD201910);the Jiangxi Natural Science Foundation for Distinguished Young Scholars(No.20212ACB216001);the Jiangxi Key Research and Development Program(No.20203BBG73063);the Jiangxi“Double Thousand Plan(No.jxsq2019101064)”to J.L.;the Thousand Young Talents Program of China and the CAS“Light of West China”Program(2021)to J.Z.;the Natural Science Foundation of Jiangxi Province(No.20224BAB216004)to H.J.;the Shanghai Science and Technology Plan Project(No.21ZR1471800)to Q.W.

摘　　要：Main protease(Mpro)serves as an indispensable factor in the life cycle of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)as well as its constantly emerging variants and is therefore considered an attractive target for antiviral drug development.Benzothiazole-based inhibitors targeting Mpro have recently been investigated by several groups and proven to be promising leads for coronaviral drug development.In the present study,we determine the crystal structures of a benzothiazole-based inhibitor,YH-53,bound to Mpro mutants from SARS-CoV-2 variants of concern(VOCs)or variants of interest(VOIs),including K90R(Beta,B.1.351),G15S(Lambda,C.37),Y54C(Delta,AY.4),M49I(Omicron,BA.5)and P132H(Omicron,B.1.1.529).The structures show that the benzothiazole group in YH-53 forms a C-S covalent bond with the sulfur atom of catalytic residue Cys145 in SARSCoV-2 Mpro mutants.Structural analysis reveals the key molecular determinants necessary for interaction and illustrates the binding mode of YH-53 to these mutant Mpros.In conclusion,structural insights from this study offer more information to develop benzothiazole-based drugs that are broader spectrum,more effective and safer.

关 键 词：SARS-CoV-2 VARIANT main protease INHIBITOR BENZOTHIAZOLE YH-53 

分 类 号：R37[医药卫生—病原生物学]