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Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CL(pro)

The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CL(pro)) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for the infection o...

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Autores principales: Ma, Ling, Xie, Yongli, Zhu, Mei, Yi, Dongrong, Zhao, Jianyuan, Guo, Saisai, Zhang, Yongxin, Wang, Jing, Li, Quanjie, Wang, Yucheng, Cen, Shan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781983/
https://www.ncbi.nlm.nih.gov/pubmed/36555652
http://dx.doi.org/10.3390/ijms232416011
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author Ma, Ling
Xie, Yongli
Zhu, Mei
Yi, Dongrong
Zhao, Jianyuan
Guo, Saisai
Zhang, Yongxin
Wang, Jing
Li, Quanjie
Wang, Yucheng
Cen, Shan
author_facet Ma, Ling
Xie, Yongli
Zhu, Mei
Yi, Dongrong
Zhao, Jianyuan
Guo, Saisai
Zhang, Yongxin
Wang, Jing
Li, Quanjie
Wang, Yucheng
Cen, Shan
author_sort Ma, Ling
collection PubMed
description The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CL(pro)) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for the infection of SARS-CoV-2. In this work, we have identified Darunavir derivatives that inhibit the 3CL(pro) through a high-throughput screening method based on a fluorescence resonance energy transfer (FRET) assay in vitro. We found that the compounds 29# and 50# containing polyphenol and caffeine derivatives as the P2 ligand, respectively, exhibited favorable anti-3CL(pro) potency with EC50 values of 6.3 μM and 3.5 μM and were shown to bind to SARS-CoV-2 3CL(pro) in vitro. Moreover, we analyzed the binding mode of the DRV in the 3CL(pro) through molecular docking. Importantly, 29# and 50# exhibited a similar activity against the protease in Omicron variants. The inhibitory effect of compounds 29# and 50# on the SARS-CoV-2 3CL(pro) warrants that they are worth being the template to design functionally improved inhibitors for the treatment of COVID-19.
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spelling pubmed-97819832022-12-24 Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CL(pro) Ma, Ling Xie, Yongli Zhu, Mei Yi, Dongrong Zhao, Jianyuan Guo, Saisai Zhang, Yongxin Wang, Jing Li, Quanjie Wang, Yucheng Cen, Shan Int J Mol Sci Article The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CL(pro)) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for the infection of SARS-CoV-2. In this work, we have identified Darunavir derivatives that inhibit the 3CL(pro) through a high-throughput screening method based on a fluorescence resonance energy transfer (FRET) assay in vitro. We found that the compounds 29# and 50# containing polyphenol and caffeine derivatives as the P2 ligand, respectively, exhibited favorable anti-3CL(pro) potency with EC50 values of 6.3 μM and 3.5 μM and were shown to bind to SARS-CoV-2 3CL(pro) in vitro. Moreover, we analyzed the binding mode of the DRV in the 3CL(pro) through molecular docking. Importantly, 29# and 50# exhibited a similar activity against the protease in Omicron variants. The inhibitory effect of compounds 29# and 50# on the SARS-CoV-2 3CL(pro) warrants that they are worth being the template to design functionally improved inhibitors for the treatment of COVID-19. MDPI 2022-12-16 /pmc/articles/PMC9781983/ /pubmed/36555652 http://dx.doi.org/10.3390/ijms232416011 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ma, Ling
Xie, Yongli
Zhu, Mei
Yi, Dongrong
Zhao, Jianyuan
Guo, Saisai
Zhang, Yongxin
Wang, Jing
Li, Quanjie
Wang, Yucheng
Cen, Shan
Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CL(pro)
title Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CL(pro)
title_full Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CL(pro)
title_fullStr Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CL(pro)
title_full_unstemmed Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CL(pro)
title_short Identification of Darunavir Derivatives for Inhibition of SARS-CoV-2 3CL(pro)
title_sort identification of darunavir derivatives for inhibition of sars-cov-2 3cl(pro)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781983/
https://www.ncbi.nlm.nih.gov/pubmed/36555652
http://dx.doi.org/10.3390/ijms232416011
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