期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
卷 187, 期 -, 页码 976-987出版社
ELSEVIER
DOI: 10.1016/j.ijbiomac.2021.07.167
关键词
SARS-CoV-2 3CL(pro); Ampelopsis grossedentata extract; Covalent inhibitors
资金
- National Key Research and Development Program of China [2020YFC0845400]
- NSF of China [81922070, 81973286, 81860614]
- Shanghai Science and Technology Innovation Action Plans - Shanghai Science and Technology Committee [20S21901500, 20S21900900]
- Three-year Action Plan of Shanghai TCM Development [ZY-(2018-2020)-CCCX-5001]
- Shuguang Program [18SG40]
- Project on the Prevention and Treatment of COVID-19 with Chinese and Western Medicines - Shanghai Education Development Foundation
- Shanghai Municipal Education Commission
- Program of Shanghai Academic/Technology Research Leader [18XD1403600]
- Program for Key Research and Development of Xinjiang Province [2017B03013]
The study demonstrated that flavonoids in Ampelopsis grossedentata extract strongly and time-dependently inhibit SARS-CoV-2 3C-like protease. Flavonoids such as myricetin and dihydromyricetin were identified as key constituents with significant inhibitory effects on SARS-CoV-2 3C-like protease.
Coronavirus 3C-like protease (3CL(pro)) is a crucial target for treating coronavirus diseases including COVID-19. Our preliminary screening showed that Ampelopsis grossedentata extract (AGE) displayed potent SARS-CoV-2-3CL(pro) inhibitory activity, but the key constituents with SARS-CoV-2-3CL(pro )inhibitory effect and their mechanisms were unrevealed. Herein, a practical strategy via integrating bioactivity-guided fractionation and purification, mass spectrometry-based peptide profiling and time-dependent biochemical assay, was applied to identify the crucial constituents in AGE and to uncover their inhibitory mechanisms. The results demonstrated that the flavonoid-rich fractions (10-17.5 min) displayed strong SARS-CoV-2-3CL(pro) inhibitory activities, while the constituents in these fractions were isolated and their SARS-CoV-2-3CL(pro) inhibitory activities were investigated. Among all isolated flavonoids, dihydromyricetin, isodihydromyricetin and myricetin strongly inhibited SARS-CoV-2 3CL(pro) in a time-dependent manner. Further investigations demonstrated that myricetin could covalently bind on SARS-CoV-2 3CL(pro) at Cys300 and Cys44, while dihydromyricetin and isodihydromyricetin covalently bound at Cys300. Covalent docking coupling with molecular dynamics simulations showed the detailed interactions between the orthoquinone form of myricetin and two covalent binding sites (surrounding Cys300 and Cys44) of SARS-CoV-2 3CL(pro). Collectively, the flavonoids in AGE strongly and time-dependently inhibit SARS-CoV-2 3CL(pro) while the newly identified SARS-CoV-2 3CL(pro) inhibitors in AGE offer promising lead compounds for developing novel antiviral agents.
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