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The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus

The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate as an inhibitor of Mpro. Our do...

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Autores principales: Qiao, Zhen, Wei, Ningning, Jin, Lin, Zhang, Hongyi, Luo, Jiajie, Zhang, Yanru, Wang, KeWei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Published by Elsevier Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556866/
https://www.ncbi.nlm.nih.gov/pubmed/34740055
http://dx.doi.org/10.1016/j.bioorg.2021.105455
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author Qiao, Zhen
Wei, Ningning
Jin, Lin
Zhang, Hongyi
Luo, Jiajie
Zhang, Yanru
Wang, KeWei
author_facet Qiao, Zhen
Wei, Ningning
Jin, Lin
Zhang, Hongyi
Luo, Jiajie
Zhang, Yanru
Wang, KeWei
author_sort Qiao, Zhen
collection PubMed
description The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate as an inhibitor of Mpro. Our docking of ebselen to the binding pocket of Mpro crystal structure suggests a noncovalent interaction for improvement of potency, antiviral activity and selectivity. To test this hypothesis, we designed and synthesized ebselen derivatives aimed at enhancing their non-covalent bonds within Mpro. The inhibition of Mpro by ebselen derivatives (0.3 μM) was screened in both HPLC and FRET assays. Nine ebselen derivatives (EBs) exhibited stronger inhibitory effect on Mpro with IC(50) of 0.07–0.38 μM. Further evaluation of three derivatives showed that EB2-7 exhibited the most potent inhibition of SARS-CoV-2 viral replication with an IC(50) value of 4.08 µM in HPAepiC cells, as compared to the prototype ebselen at 24.61 μM. Mechanistically, EB2-7 functions as a noncovalent Mpro inhibitor in LC-MS/MS assay. Taken together, our identification of ebselen derivatives with improved antiviral activity may lead to developmental potential for treatment of COVID-19 and SARS-CoV-2 infection.
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spelling pubmed-85568662021-11-01 The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus Qiao, Zhen Wei, Ningning Jin, Lin Zhang, Hongyi Luo, Jiajie Zhang, Yanru Wang, KeWei Bioorg Chem Article The main protease (Mpro or 3CLpro) of SARS-CoV-2 virus is a cysteine enzyme critical for viral replication and transcription, thus indicating a potential target for antiviral therapy. A recent repurposing effort has identified ebselen, a multifunctional drug candidate as an inhibitor of Mpro. Our docking of ebselen to the binding pocket of Mpro crystal structure suggests a noncovalent interaction for improvement of potency, antiviral activity and selectivity. To test this hypothesis, we designed and synthesized ebselen derivatives aimed at enhancing their non-covalent bonds within Mpro. The inhibition of Mpro by ebselen derivatives (0.3 μM) was screened in both HPLC and FRET assays. Nine ebselen derivatives (EBs) exhibited stronger inhibitory effect on Mpro with IC(50) of 0.07–0.38 μM. Further evaluation of three derivatives showed that EB2-7 exhibited the most potent inhibition of SARS-CoV-2 viral replication with an IC(50) value of 4.08 µM in HPAepiC cells, as compared to the prototype ebselen at 24.61 μM. Mechanistically, EB2-7 functions as a noncovalent Mpro inhibitor in LC-MS/MS assay. Taken together, our identification of ebselen derivatives with improved antiviral activity may lead to developmental potential for treatment of COVID-19 and SARS-CoV-2 infection. Published by Elsevier Inc. 2021-12 2021-10-30 /pmc/articles/PMC8556866/ /pubmed/34740055 http://dx.doi.org/10.1016/j.bioorg.2021.105455 Text en © 2021 Published by Elsevier Inc. 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
Qiao, Zhen
Wei, Ningning
Jin, Lin
Zhang, Hongyi
Luo, Jiajie
Zhang, Yanru
Wang, KeWei
The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus
title The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus
title_full The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus
title_fullStr The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus
title_full_unstemmed The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus
title_short The Mpro structure-based modifications of ebselen derivatives for improved antiviral activity against SARS-CoV-2 virus
title_sort mpro structure-based modifications of ebselen derivatives for improved antiviral activity against sars-cov-2 virus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556866/
https://www.ncbi.nlm.nih.gov/pubmed/34740055
http://dx.doi.org/10.1016/j.bioorg.2021.105455
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