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

Chong Huang; Rui Zeng; Jingxin Qiao; Baoxue Quan; Ronghua Luo; Qiao Huang; Nihong Guo; Yueyue Li; Xinyan Long; Ronggang Ma; Anjie Xia; Zhen Fang; Yifei Wang; Yueshan Li; Yongtang Zheng; Linli Li; Jian Lei; Shengyong Yang

doi:10.1016/j.ejmech.2023.115657

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. Epub 2023 Jul 20.

Authors

Chong Huang¹, Rui Zeng¹, Jingxin Qiao¹, Baoxue Quan¹, Ronghua Luo², Qiao Huang³, Nihong Guo³, Yueyue Li¹, Xinyan Long², Ronggang Ma¹, Anjie Xia¹, Zhen Fang¹, Yifei Wang¹, Yueshan Li¹, Yongtang Zheng⁴, Linli Li⁵, Jian Lei⁶, Shengyong Yang⁷

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: zhengyt@mail.kiz.ac.cn.
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: lilinli@scu.edu.cn.
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: leijian@scu.edu.cn.
⁷ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: yangsy@scu.edu.cn.

PMID: 37517202
DOI: 10.1016/j.ejmech.2023.115657

Abstract

The SARS-CoV-2 main protease (M^pro, also named 3CL^pro) 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 M^pro inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent M^pro inhibitor (27h) with an IC₅₀ value of 10.9 nM. The crystal structure of M^pro 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 M^pro 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 M^pro and deserves further in-depth studies.

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

MeSH terms

Antiviral Agents / chemistry
COVID-19*
Humans
Molecular Docking Simulation
Protease Inhibitors / chemistry
SARS-CoV-2 / metabolism
Structure-Activity Relationship
Viral Nonstructural Proteins

Substances

3C-like proteinase, SARS-CoV-2
Protease Inhibitors
Viral Nonstructural Proteins
Antiviral Agents