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

Qiao Huang; Baoxue Quan; Yan Chen; Xiu Zhao; Yanmei Zhou; Chong Huang; Jingxin Qiao; Yifei Wang; Yueyue Li; Shengyong Yang; Jian Lei; Linli Li

doi:10.1016/j.bioorg.2023.107001

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

Bioorg Chem. 2024 Feb:143:107001. doi: 10.1016/j.bioorg.2023.107001. Epub 2023 Dec 6.

Authors

Qiao Huang¹, Baoxue Quan², Yan Chen², Xiu Zhao², Yanmei Zhou², Chong Huang², Jingxin Qiao², Yifei Wang², Yueyue Li², Shengyong Yang³, Jian Lei⁴, Linli Li⁵

Affiliations

¹ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
² Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
³ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China.
⁴ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
⁵ Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: [email protected].

PMID: 38101266
DOI: 10.1016/j.bioorg.2023.107001

Abstract

Although the SARS-CoV-2 pandemic has ended, multiple sporadic cases still exist, posing a request for more antivirals. The main protease (M^pro) 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 α-ketoamide-containing M^pro 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 M^pro 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.

Keywords: Covalent inhibitor; Main protease; Protein structure; SARS-CoV-2.

MeSH terms

Antiviral Agents / pharmacology
COVID-19*
Coronavirus 3C Proteases*
Humans
Molecular Docking Simulation
Protease Inhibitors / pharmacology
SARS-CoV-2*

Substances

3C-like proteinase, SARS-CoV-2
Antiviral Agents
Protease Inhibitors
Coronavirus 3C Proteases