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

Wang，Feng1; Liu，Donglan2,3; Gao，Dingding1; Yuan，Jinwei2; Zhao，Jingxian2; Yuan，Shuai6; Cen，Yixin1; Lin，Guo Qiang1; Zhao，Jincun2,3,4,5; Tian，Ping1

2024-04-01

10.1016/j.ijbiomac.2024.130377

International Journal of Biological Macromolecules   影响因子和分区

0141-8130

1879-0003

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 (3CL) 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 3CL, 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 3CL with an IC value of 4.18 μM. Further studies revealed that the catechol core is essential for activity and can covalently bind to SARS-CoV-2 3CL. Among other 45 catechol derivatives, wedelolactone, capsazepine and brazilin showed better SARS-CoV-2 3CL inhibitory activities with IC 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 PL, cathepsin B and cathepsin L). Subsequently, the binding affinity between brazilin and SARS-CoV-2 3CL 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 EC 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.

Antiviral activities Catechol derivatives Covalent inhibitors SARS-CoV-2 3CLpro

SCI ; EI

英语

其他

BIOLOGY & BIOCHEMISTRY

2-s2.0-85186505615

Scopus

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
3.Guangzhou National Laboratory,Guangzhou International Bio-Island,Guangzhou,Guangdong,510320,China
4.Shanghai Institute for Advanced Immunochemical Studies,School of Life Science and Technology,ShanghaiTech University,Shanghai,201210,China
5.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
6.Health and Quarantine Laboratory,Guangzhou Customs District Technology Center,Guangzhou,510700,China

Wang，Feng,Liu，Donglan,Gao，Dingding,et al. Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors[J]. International Journal of Biological Macromolecules,2024,264.

Wang，Feng.,Liu，Donglan.,Gao，Dingding.,Yuan，Jinwei.,Zhao，Jingxian.,...&Tian，Ping.(2024).Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors.International Journal of Biological Macromolecules,264.

Wang，Feng,et al."Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors".International Journal of Biological Macromolecules 264(2024).