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Discovery and characterization of the covalent SARS-CoV-2 3CL(pro) inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches
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 w...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier GmbH.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052880/ https://www.ncbi.nlm.nih.gov/pubmed/37037086 http://dx.doi.org/10.1016/j.phymed.2023.154796 |
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author | Zhang, Ya-Ni Zhu, Guang-Hao Liu, Wei Xiong, Yuan Hu, Qing Zhuang, Xiao-Yu Jia, Gui-Hua Zhang, Wei-Dong Ge, Guang-Bo |
author_facet | Zhang, Ya-Ni Zhu, Guang-Hao Liu, Wei Xiong, Yuan Hu, Qing Zhuang, Xiao-Yu Jia, Gui-Hua Zhang, Wei-Dong Ge, Guang-Bo |
author_sort | Zhang, Ya-Ni |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10052880 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier GmbH. |
record_format | MEDLINE/PubMed |
spelling | pubmed-100528802023-03-29 Discovery and characterization of the covalent SARS-CoV-2 3CL(pro) inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches Zhang, Ya-Ni Zhu, Guang-Hao Liu, Wei Xiong, Yuan Hu, Qing Zhuang, Xiao-Yu Jia, Gui-Hua Zhang, Wei-Dong Ge, Guang-Bo Phytomedicine Original Article 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. Elsevier GmbH. 2023-06 2023-03-29 /pmc/articles/PMC10052880/ /pubmed/37037086 http://dx.doi.org/10.1016/j.phymed.2023.154796 Text en © 2023 Elsevier GmbH. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Original Article Zhang, Ya-Ni Zhu, Guang-Hao Liu, Wei Xiong, Yuan Hu, Qing Zhuang, Xiao-Yu Jia, Gui-Hua Zhang, Wei-Dong Ge, Guang-Bo Discovery and characterization of the covalent SARS-CoV-2 3CL(pro) inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches |
title | Discovery and characterization of the covalent SARS-CoV-2 3CL(pro) inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches |
title_full | Discovery and characterization of the covalent SARS-CoV-2 3CL(pro) inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches |
title_fullStr | Discovery and characterization of the covalent SARS-CoV-2 3CL(pro) inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches |
title_full_unstemmed | Discovery and characterization of the covalent SARS-CoV-2 3CL(pro) inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches |
title_short | Discovery and characterization of the covalent SARS-CoV-2 3CL(pro) inhibitors from Ginkgo biloba extract via integrating chemoproteomic and biochemical approaches |
title_sort | discovery and characterization of the covalent sars-cov-2 3cl(pro) inhibitors from ginkgo biloba extract via integrating chemoproteomic and biochemical approaches |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052880/ https://www.ncbi.nlm.nih.gov/pubmed/37037086 http://dx.doi.org/10.1016/j.phymed.2023.154796 |
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