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Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals
The emerging COVID-19 pandemic generated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has severely threatened human health. The main protease (M(pro)) of SARS-CoV-2 is promising target for antiviral drugs, which plays a vital role for viral duplication. Development of the inhibito...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014651/ https://www.ncbi.nlm.nih.gov/pubmed/35462235 http://dx.doi.org/10.1016/j.bioorg.2022.105799 |
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author | Xu, Yin-Sui Chigan, Jia-Zhu Li, Jia-Qi Ding, Huan-Huan Sun, Le-Yun Liu, Lu Hu, Zhenxin Yang, Ke-Wu |
author_facet | Xu, Yin-Sui Chigan, Jia-Zhu Li, Jia-Qi Ding, Huan-Huan Sun, Le-Yun Liu, Lu Hu, Zhenxin Yang, Ke-Wu |
author_sort | Xu, Yin-Sui |
collection | PubMed |
description | The emerging COVID-19 pandemic generated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has severely threatened human health. The main protease (M(pro)) of SARS-CoV-2 is promising target for antiviral drugs, which plays a vital role for viral duplication. Development of the inhibitor against M(pro) is an ideal strategy to combat COVID-19. In this work, twenty-three hydroxamates 1a-i and thiosemicarbazones 2a-n were identified by FRET screening to be the potent inhibitors of M(pro), which exhibited more than 94% (except 1c) and more than 69% inhibition, and an IC(50) value in the range of 0.12–31.51 and 2.43–34.22 μM, respectively. 1a and 2b were found to be the most effective inhibitors in the hydroxamates and thiosemicarbazones, with an IC(50) of 0.12 and 2.43 μM, respectively. Enzyme kinetics, jump dilution and thermal shift assays revealed that 2b is a competitive inhibitor of M(pro), while 1a is a time-dependently inhibitor; 2b reversibly but 1a irreversibly bound to the target; the binding of 2b increased but 1a decreased stability of the target, and DTT assays indicate that 1a is the promiscuous cysteine protease inhibitor. Cytotoxicity assays showed that 1a has low, but 2b has certain cytotoxicity on the mouse fibroblast cells (L929). Docking studies revealed that the benzyloxycarbonyl carbon of 1a formed thioester with Cys145, while the phenolic hydroxyl oxygen of 2b formed H-bonds with Cys145 and Asn142. This work provided two promising scaffolds for the development of M(pro) inhibitors to combat COVID-19. |
format | Online Article Text |
id | pubmed-9014651 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90146512022-04-18 Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals Xu, Yin-Sui Chigan, Jia-Zhu Li, Jia-Qi Ding, Huan-Huan Sun, Le-Yun Liu, Lu Hu, Zhenxin Yang, Ke-Wu Bioorg Chem Article The emerging COVID-19 pandemic generated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has severely threatened human health. The main protease (M(pro)) of SARS-CoV-2 is promising target for antiviral drugs, which plays a vital role for viral duplication. Development of the inhibitor against M(pro) is an ideal strategy to combat COVID-19. In this work, twenty-three hydroxamates 1a-i and thiosemicarbazones 2a-n were identified by FRET screening to be the potent inhibitors of M(pro), which exhibited more than 94% (except 1c) and more than 69% inhibition, and an IC(50) value in the range of 0.12–31.51 and 2.43–34.22 μM, respectively. 1a and 2b were found to be the most effective inhibitors in the hydroxamates and thiosemicarbazones, with an IC(50) of 0.12 and 2.43 μM, respectively. Enzyme kinetics, jump dilution and thermal shift assays revealed that 2b is a competitive inhibitor of M(pro), while 1a is a time-dependently inhibitor; 2b reversibly but 1a irreversibly bound to the target; the binding of 2b increased but 1a decreased stability of the target, and DTT assays indicate that 1a is the promiscuous cysteine protease inhibitor. Cytotoxicity assays showed that 1a has low, but 2b has certain cytotoxicity on the mouse fibroblast cells (L929). Docking studies revealed that the benzyloxycarbonyl carbon of 1a formed thioester with Cys145, while the phenolic hydroxyl oxygen of 2b formed H-bonds with Cys145 and Asn142. This work provided two promising scaffolds for the development of M(pro) inhibitors to combat COVID-19. Elsevier Inc. 2022-07 2022-04-18 /pmc/articles/PMC9014651/ /pubmed/35462235 http://dx.doi.org/10.1016/j.bioorg.2022.105799 Text en © 2022 Elsevier Inc. 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 | Article Xu, Yin-Sui Chigan, Jia-Zhu Li, Jia-Qi Ding, Huan-Huan Sun, Le-Yun Liu, Lu Hu, Zhenxin Yang, Ke-Wu Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals |
title | Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals |
title_full | Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals |
title_fullStr | Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals |
title_full_unstemmed | Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals |
title_short | Hydroxamate and thiosemicarbazone: Two highly promising scaffolds for the development of SARS-CoV-2 antivirals |
title_sort | hydroxamate and thiosemicarbazone: two highly promising scaffolds for the development of sars-cov-2 antivirals |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9014651/ https://www.ncbi.nlm.nih.gov/pubmed/35462235 http://dx.doi.org/10.1016/j.bioorg.2022.105799 |
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