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.
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页数：12
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