The S1'-S3' Pocket of the SARS-CoV-2 Main Protease Is Critical for Substrate Selectivity and Can Be Targeted with Covalent Inhibitors

Liu, Ming1; Li, Jihui1; Liu, Wenqi2; Yang, Ying1; Zhang, Manman1; Ye, Yuxin1; Zhu, Wenning1; Zhou, Cuiyan3; Zhai, Hongbin1; Xu, Zhengshuang1; Zhang, Guoliang2; Huang, Hao1,4

2023-09-01

10.1002/anie.202309657

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   影响因子和分区

1433-7851

1521-3773

["The main protease (Mpro) of SARS-CoV-2 is a well-characterized target for antiviral drug discovery. To date, most antiviral drug discovery efforts have focused on the S4-S1 & PRIME; pocket of Mpro; however, it is still unclear whether the S1 & PRIME;-S3 & PRIME; pocket per se can serve as a new site for drug discovery. In this study, the S1 & PRIME;-S3 & PRIME; pocket of Mpro was found to differentially recognize viral peptidyl substrates. For instance, S3 & PRIME; in Mpro strongly favors Phe or Trp, and S1 & PRIME; favors Ala. The peptidyl inhibitor D-4-77, which possesses an & alpha;-bromoacetamide warhead, was discovered to be a promising inhibitor of Mpro, with an IC50 of 0.95 & mu;M and an antiviral EC50 of 0.49 & mu;M. The Mpro/inhibitor co-crystal structure confirmed the binding mode of the inhibitor to the S1 & PRIME;-S3 & PRIME; pocket and revealed a covalent mechanism. In addition, D-4-77 functions as an immune protectant and suppresses SARS-CoV-2 Mpro-induced antagonism of the host NF-& kappa;B innate immune response. These findings indicate that the S1 & PRIME;-S3 & PRIME; pocket of SARS-CoV-2 Mpro is druggable, and that inhibiting SARS-CoV-2 Mpro can simultaneously protect human innate immunity and inhibit virion assembly.","Substrate-peptide screening for SARS-CoV-2 Mpro was performed to select suitable residues for the S1 & PRIME;-S4 & PRIME; sites of Mpro. The Ala-Ile-Phe (AIF) motif was chosen as the scaffold for discovering inhibitors that target the S1 & PRIME;-S3 & PRIME; pocket. Warhead screening and structure-activity relationship studies revealed a covalent inhibitor, D-4-77, with an & alpha;-bromoacetamide warhead that exhibited potent inhibitory activity in vitro.+image"]

Immune Protectant Inhibitor Main Protease SARS-Cov-2 Substrate Selectivity

SCI ; EI ; IC

英语

NI论文

通讯

We thank Dr. Cong Yu and Dr. Zhiyi Wei (Southern University of Science and Technology) for technical assistance in ITC experiments. We thank Dr. Ziyang Fu for assistance in structure determination. We thank Dr. Yingjie Wang at the Shenzhen Bay Laboratory f[KQTD20190929174023858] ; National Natural Science Foundation of China["JCYJ20200109140401752","GXWD20201231165807007-20200814103036001","JSGG20200225150702770","JCYJ20210324120007020"] ; null[21977009]

Chemistry

Chemistry, Multidisciplinary

WOS:001057870200001

WILEY-V C H VERLAG GMBH

20233614675834

Binding energy ; Coronavirus ; Diseases ; Immune system ; Substrates

Medicine and Pharmacology:461.6 ; Immunology:461.9.1 ; Physical Chemistry:801.4 ; Crystal Lattice:933.1.1

CHEMISTRY

Web of Science

1.Peking Univ, Sch Chem Biol & Biotechnol, Lab Ubiquitinat & Targeted Therapy, Shenzhen Grad Sch,State Key Lab Chem Oncogen,Guang, Shenzhen 518055, Guangdong, Peoples R China
2.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Shenzhen 518112, Guangdong, Peoples R China
3.Tsinghua Univ, Sch Life Sci, Natl Prot Sci Facil, Beijing 100084, Peoples R China
4.Shenzhen Bay Lab, Inst Chem Biol, Shenzhen 518132, Guangdong, Peoples R China

Liu, Ming,Li, Jihui,Liu, Wenqi,et al. The S1'-S3' Pocket of the SARS-CoV-2 Main Protease Is Critical for Substrate Selectivity and Can Be Targeted with Covalent Inhibitors[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2023,62(41).

Liu, Ming.,Li, Jihui.,Liu, Wenqi.,Yang, Ying.,Zhang, Manman.,...&Huang, Hao.(2023).The S1'-S3' Pocket of the SARS-CoV-2 Main Protease Is Critical for Substrate Selectivity and Can Be Targeted with Covalent Inhibitors.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,62(41).

Liu, Ming,et al."The S1'-S3' Pocket of the SARS-CoV-2 Main Protease Is Critical for Substrate Selectivity and Can Be Targeted with Covalent Inhibitors".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 62.41(2023).