Discovery and mechanism of action of Thonzonium bromide from an FDA-approved drug library with potent and broad-spectrum inhibitory activity against main proteases of human coronaviruses
文献类型：期刊论文
| 作者 | Wang, Ruyu2; Zhai, Guanglei1; Zhu, Guanghao2; Wang, Mengge2; Gong, Xiaoyi3; Zhang, Weidong2,4; Ge, Guangbo2; Chen, Hongzhuan2; Chen, Lili2 |
| 刊名 | BIOORGANIC CHEMISTRY
 |
| 出版日期 | 2023 |
| 卷号 | 130页码:11 |
| ISSN号 | 0045-2068 |
| 关键词 | SARS-CoV-23CLpro Thonzonium bromide Mechanism of action Broad-spectrum inhibitor |
| DOI | 10.1016/j.bioorg.2022.106264 |
| 通讯作者 | Ge, Guangbo(geguangbo@dicp.ac.cn) ; Chen, Hongzhuan(yaoli@shsmu.edu.cn) ; Chen, Lili(llchen@shutcm.edu.cn) |
| 英文摘要 | Although the effective drugs or vaccines have been developed to prevent the spread of the severe acute respi-ratory syndrome coronavirus 2 (SARS-CoV-2), their efficacy may be limited for the viral evolution and immune escape. Thus, it is urgently needed to develop the novel broad-spectrum antiviral agents to control the coro-navirus disease 2019 (COVID-19) global pandemic. The 3C-like protease (3CLpro) is a highly conserved cysteine proteinase that plays a pivotal role in processing the viral polyprotein to create non-structural proteins (nsps) for replication and transcription of SARS-CoV-2, making it an attractive antiviral target for developing broad-spectrum antiviral agents against SARS-CoV-2. In this study, we identified Thonzonium bromide as an inhibi-tor of SARS-CoV-2 3CLpro with an IC50 value of 2.04 +/- 0.25 mu M by fluorescence resonance energy transfer (FRET)-based enzymatic inhibition assay from the FDA-approved drug library. Next, we determined the inhib-itory activity of Thonzonium bromide analogues against SARS-CoV-2 3CLpro and analyzed their structur-e-activity relationship (SAR). Interestingly, Thonzonium bromide showed better inhibitory activity than other analogues. Further fluorescence quenching assay, enzyme kinetics analysis, circular dichroism (CD) analysis and molecular docking studies showed that Thonzonium bromide inhibited SARS-CoV-2 3CLpro activity by firmly occupying the catalytic site and inducing conformational changes of the protease. In addition, Thonzonium bromide didn't exhibit inhibitory activity on human chymotrypsin C (CTRC) and Dipeptidyl peptidase IV (DPP -IV), indicating that it had a certain selectivity. Finally, we measured the inhibitory activities of Thonzonium bromide against 3CLpro of SARS-CoV, MERS-CoV and HCoV-229E and found that it had the broad-spectrum inhibitory activity against the proteases of human coronaviruses. These results provide the possible mecha-nism of action of Thonzonium bromide, highlighting its potential efficacy against multiple human coronaviruses. |
| WOS关键词 | RESPIRATORY SYNDROME-CORONAVIRUS ; CIRCULAR-DICHROISM SPECTRA ; IDENTIFICATION ; SPECIFICITIES ; FLUORESCENCE ; REPLICATION ; BINDING ; OXYGEN ; PROBE |
| 资助项目 | Shanghai Municipal Science and Technology Major Project[82141203] ; National Natural Science Foun-dation of China[ZY (2021-2023) -0103] ; Shanghai Municipal Health Commission ; [ZD2021CY001] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| WOS记录号 | WOS:000890457800004 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/304518]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Ge, Guangbo; Chen, Hongzhuan; Chen, Lili |
| 作者单位 | 1.Shanghai HighsLab Therapeut Inc, Shanghai 201203, Peoples R China 2.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai Frontiers Sci Ctr TCM Chem Biol, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Beijing 201203, Peoples R China 4.Shanghai Univ Tradit Chinese Med, Shanghai Inst Infect Dis & Biosafety, Inst Interdisciplinary Integrat Med Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Ruyu,Zhai, Guanglei,Zhu, Guanghao,et al. Discovery and mechanism of action of Thonzonium bromide from an FDA-approved drug library with potent and broad-spectrum inhibitory activity against main proteases of human coronaviruses[J]. BIOORGANIC CHEMISTRY,2023,130:11. |
| APA | Wang, Ruyu.,Zhai, Guanglei.,Zhu, Guanghao.,Wang, Mengge.,Gong, Xiaoyi.,...&Chen, Lili.(2023).Discovery and mechanism of action of Thonzonium bromide from an FDA-approved drug library with potent and broad-spectrum inhibitory activity against main proteases of human coronaviruses.BIOORGANIC CHEMISTRY,130,11. |
| MLA | Wang, Ruyu,et al."Discovery and mechanism of action of Thonzonium bromide from an FDA-approved drug library with potent and broad-spectrum inhibitory activity against main proteases of human coronaviruses".BIOORGANIC CHEMISTRY 130(2023):11. |
入库方式： OAI收割
来源：上海药物研究所
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