Discovery of α-Ketoamide inhibitors of SARS-CoV-2 main protease derived from quaternized P1 groups

被引：2

作者：

Huang, Qiao ^{[1
]}

Quan, Baoxue ^{[2
,3
]}

Chen, Yan ^{[2
,3
]}

Zhao, Xiu ^{[2
,3
]}

Zhou, Yanmei ^{[2
,3
]}

Huang, Chong ^{[2
,3
]}

Qiao, Jingxin ^{[2
,3
]}

Wang, Yifei ^{[2
,3
]}

Li, Yueyue ^{[2
,3
]}

Yang, Shengyong ^{[2
,3
,4
]}

Lei, Jian ^{[2
,3
,5
]}

Li, Linli ^{[1
]}

机构：

[1] Sichuan Univ, West China Sch Pharm, Key Lab Drug Targeting & Drug Delivery Syst, Minist Educ, Chengdu 610041, Sichuan, Peoples R China

[2] Sichuan Univ, West China Hosp, Canc Ctr, Dept Biotherapy, Chengdu 610041, Sichuan, Peoples R China

[3] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China

[4] Frontier Med Ctr, Tianfu Jincheng Lab, Chengdu 610212, Sichuan, Peoples R China

[5] Sichuan Univ, West China Hosp, Natl Clin Res Ctr Geriatr, Chengdu 610041, Sichuan, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2024年 / 143卷

基金：

中国国家自然科学基金;

关键词：

SARS-CoV-2; Main protease; Covalent inhibitor; Protein structure; POTENT;

D O I：

10.1016/j.bioorg.2023.107001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Although the SARS-CoV-2 pandemic has ended, multiple sporadic cases still exist, posing a request for more antivirals. The main protease (Mpro) of SARS-CoV-2, a key enzyme for viral replication, is an attractive target for drug development. Here, we report the discovery of a new potent alpha-ketoamide-containing Mpro inhibitor, N-((R)1-cyclohexyl-2-(((R)-3-methoxy-1-oxo-1-((1-(2-oxo-2-((thiazol-2-ylmethyl)amino)acetyl)cyclobutyl)amino) propan-2-yl)amino)-2-oxoethyl)-4,4-difluorocyclohexane-1-carboxamide (20j). This compound presented promising enzymatic inhibitory activity against SARS-CoV-2 Mpro with an IC50 value of 19.0 nM, and an excellent antiviral activity in cell-based assay with an EC50 value of 138.1 nM. This novel covalent inhibitor may be used as a lead compound for subsequent drug discovery against SARS-CoV-2.

引用

页数：12

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