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
  • 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 (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.
Products