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

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.
Qiao Huang 1,  Baoxue Quan 2,  Yan Chen 2,  Xiu Zhao 2,  Yanmei Zhou 2,  Chong Huang 2,  Jingxin Qiao 2,  Yifei Wang 2,  Yueyue Li 2,  Shengyong Yang 3,  Jian Lei 4,  Linli Li 5
Affiliations

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: lilinli@scu.edu.cn.
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 (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 α-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.

Keywords

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

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