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  3. Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease

Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease

  • Eur J Med Chem. 2023 Nov 5;259:115657. doi: 10.1016/j.ejmech.2023.115657.
Chong Huang 1,  Rui Zeng 1,  Jingxin Qiao 1,  Baoxue Quan 1,  Ronghua Luo 2,  Qiao Huang 3,  Nihong Guo 3,  Yueyue Li 1,  Xinyan Long 2,  Ronggang Ma 1,  Anjie Xia 1,  Zhen Fang 1,  Yifei Wang 1,  Yueshan Li 1,  Yongtang Zheng 4,  Linli Li 5,  Jian Lei 6,  Shengyong Yang 7
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 2 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
  • 3 Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 4 Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China. Electronic address: [email protected].
  • 5 Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: [email protected].
  • 6 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. Electronic address: [email protected].
  • 7 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: [email protected].
PMID: 37517202 DOI: 10.1016/j.ejmech.2023.115657
Abstract

The SARS-CoV-2 main protease (Mpro, also named 3CLpro) is a promising Antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of α-ketoamide derivatives as a new class of SARS-CoV-2 Mpro inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent Mpro inhibitor (27h) with an IC50 value of 10.9 nM. The crystal structure of Mpro in complex with 27h revealed that α-ketoamide warhead covalently bound to Cys145s of the protease. In an in vitro Antiviral assay, 27h showed excellent activity with an EC50 value of 43.6 nM, comparable to the positive control, Nirmatrelvir. This compound displayed high target specificity for Mpro against human proteases and low toxicity. It also possesses favorable pharmacokinetic properties. Overall, compound 27h could be a promising lead compound for drug discovery targeting SARS-CoV-2 Mpro and deserves further in-depth studies.

Keywords

M(pro) inhibitor; SARS-CoV-2; Structure-activity relationship; α-ketoamide derivatives.

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