Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors
发布时间：2025-11
点击次数：
- 发布时间：
- 2025-11
- 影响因子：
- 8.5
- DOI码：
- 10.1016/j.ijbiomac.2024.130377
- 论文名称：
- Discovery of natural catechol derivatives as covalent SARS-CoV-2 3CLpro inhibitors
- 发表刊物：
- INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
- 摘要：
- 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 inhouse 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 mu M. 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 mu M, 1.95 mu M and 1.18 mu M, 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 mu M. 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 mu M and 5.24 +/- 0.21 mu M 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.
- 第一作者：
- wangfeng,刘冬兰
- 论文类型：
- 期刊论文
- 通讯作者：
- gaodingding,cenyixin,林国强,赵金存,田平
- 卷号：
- 264
- ISSN号：
- 0141-8130
- 是否译文：
- 否
- 发表时间：
- 2024-04
- 他引次数：
- 4