2. Academic Validation
  3. Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors

Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors

  • Int J Biol Macromol. 2024 Feb 21;264(Pt 1):130377. doi: 10.1016/j.ijbiomac.2024.130377.
Feng Wang 1,  Donglan Liu 2,  Dingding Gao 3,  Jinwei Yuan 4,  Jingxian Zhao 4,  Shuai Yuan 5,  Yixin Cen 6,  Guo-Qiang Lin 7,  Jincun Zhao 8,  Ping Tian 9
Affiliations

Affiliations

  • 1 The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China; Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong 510320, China.
  • 3 The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: gaodingding@shutcm.edu.cn.
  • 4 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China.
  • 5 Health and Quarantine Laboratory, Guangzhou Customs District Technology Center, Guangzhou 510700, China.
  • 6 The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: yixincen@shutcm.edu.cn.
  • 7 The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: lingq@sioc.ac.cn.
  • 8 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China; Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, Guangdong 510320, China; Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, Shenzhen, China. Electronic address: zhaojincun@gird.cn.
  • 9 The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: tianping@shutcm.edu.cn.
PMID: 38395279 DOI: 10.1016/j.ijbiomac.2024.130377
Abstract

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a threat to public health, and extensive research by scientists worldwide has also prompted the development of Antiviral therapies. The 3C-like Protease (3CLpro) is critical for SARS-CoV-2 replication and acts as an effective target for drug development. To date, numerous of Natural Products have been reported to exhibit inhibitory effects on 3CLpro, which encourages us to identify other novel inhibitors and elucidate their mechanism of action. In this study, we first screened an in-house compound library of 101 Natural Products using FRET assay, and found that oleuropein showed good inhibitory activity against SARS CoV-2 3CLpro with an IC50 value of 4.18 μM. Further studies revealed that the catechol core is essential for activity and can covalently bind to SARS-CoV-2 3CLpro. Among other 45 catechol derivatives, wedelolactone, capsazepine and brazilin showed better SARS-CoV-2 3CLpro inhibitory activities with IC50 values of 1.35 μM, 1.95 μM and 1.18 μM, respectively. These catechol derivatives were verified to be irreversible covalent inhibitors by time-dependent experiments, enzymatic kinetic studies, dilution and dialysis assays. It also exhibited good selectivity towards different cysteine proteases (SARS-CoV-2 PLpro, Cathepsin B and Cathepsin L). Subsequently, the binding affinity between brazilin and SARS-CoV-2 3CLpro was determined by SPR assay with KD value of 0.80 μM. Molecular dynamic (MD) simulations study showed the binding mode of brazilin in the target protein. In particular, brazilin displayed good anti-SARS-CoV-2 activity in A549-hACE2-TMPRSS2 cells with EC50 values of 7.85 ± 0.20 μM and 5.24 ± 0.21 μM for full time and post-infection treatments, respectively. This study provides a promising lead compound for the development of novel anti-SARS-CoV-2 drugs.

Keywords

Antiviral activities; Catechol derivatives; Covalent inhibitors; SARS-CoV-2 3CL(pro).

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