Discovery and characterization of the covalent SARS-CoV-2 3CL pro inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches.

Autor: Zhang YN; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China., Zhu GH; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China., Liu W; Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China., Xiong Y; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China., Hu Q; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Clinical Pharmacy Center, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China., Zhuang XY; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China., Jia GH; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China., Zhang WD; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China., Ge GB; Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: geguangbo@shutcm.edu.cn.
Jazyk: angličtina
Zdroj: Phytomedicine : international journal of phytotherapy and phytopharmacology [Phytomedicine] 2023 Jun; Vol. 114, pp. 154796. Date of Electronic Publication: 2023 Mar 29.
DOI: 10.1016/j.phymed.2023.154796
Abstrakt: Background: The 3C-like proteases (3CL pro s) are cysteine-rich homodimeric proteins and can be covalently modified by numerous natural and synthetic compounds, which in turn, block the proteolytic activity or the formation of enzymatically active dimeric forms. Although herbal medicines have been widely used to treat COVID-19, identification of the key herbal constituents that can covalently modify the 3CL pro s in β-coronaviruses (CoVs) remains a big challenge.
Aims: To construct a comprehensive approach for efficient discovering the covalent SARS-CoV-2 3CL pro inhibitors from herbal medicines. To decipher the key anti-SARS-CoV-2 3CL pro constituents in Ginkgo biloba extract 50 (GBE50) and to study their anti-SARS-CoV-2 3CL pro mechanisms.
Methods: SARS-CoV-2 3CL pro inhibition assay including time-dependent inhibition assays and inactivation kinetic analyses were conducted using a fluorescence-based biochemical assay. The constituents in GBE50 were analyzed by UHPLC-Q-Exactive Orbitrap HRMS. The peptides modified by herbal constituents were characterized by using nanoLC-MS/MS.
Results: Following testing the anti-SARS-CoV-2 3CL pro effects of 104 herbal medicines, it was found that Ginkgo biloba extract 50 (GBE50) potently inhibited SARS-CoV-2 3CL pro in dose- and time-dependent manners. A total of 38 constituents were identified from GBE50 by UHPLC-Q-Exactive Orbitrap HRMS, while 26 peptides modified by 18 constituents were identified by chemoproteomic profiling. The anti-SARS-CoV-2 3CL pro effects of 18 identified covalent inhibitors were then validated by performing time-dependent inhibition assays. The results clearly demonstrated that most tested constituents showed time-dependent inhibition on SARS-CoV-2 3CL pro , while gallocatechin and sciadopitysin displayed the most potent anti-SARS-CoV-2 3CL pro effects.
Conclusion: Collectively, GBE50 and some constituents in this herbal product could strongly inhibit SARS-CoV-2 3CL pro in dose- and time-dependent manner. Gallocatechin and sciadopitysin were identified as potent SARS-CoV-2 3CL pro inhibitors, which offers promising lead compounds for the development of novel anti-SARS-CoV-2 drugs.
Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests.
(Copyright © 2023. Published by Elsevier GmbH.)
Databáze: MEDLINE
Externí odkaz: