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Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection

Covalent inhibitors targeting the main protease (M(pro), or 3CLpro) of SARS-CoV-2 have shown promise in preclinical investigations. Herein, we report the discovery of two new series of molecules that irreversibly bind to SARS-CoV-2 M(pro). These acrylamide containing molecules were discovered using...

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Autores principales: Ge, Rui, Shen, Zuyuan, Yin, Jian, Chen, Wenhua, Zhang, Qi, An, Yulong, Tang, Dewei, Satz, Alexander L., Su, Wenji, Kuai, Letian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Author(s). Published by Elsevier Inc. on behalf of Society for Laboratory Automation and Screening. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767972/
https://www.ncbi.nlm.nih.gov/pubmed/35063690
http://dx.doi.org/10.1016/j.slasd.2022.01.001
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author Ge, Rui
Shen, Zuyuan
Yin, Jian
Chen, Wenhua
Zhang, Qi
An, Yulong
Tang, Dewei
Satz, Alexander L.
Su, Wenji
Kuai, Letian
author_facet Ge, Rui
Shen, Zuyuan
Yin, Jian
Chen, Wenhua
Zhang, Qi
An, Yulong
Tang, Dewei
Satz, Alexander L.
Su, Wenji
Kuai, Letian
author_sort Ge, Rui
collection PubMed
description Covalent inhibitors targeting the main protease (M(pro), or 3CLpro) of SARS-CoV-2 have shown promise in preclinical investigations. Herein, we report the discovery of two new series of molecules that irreversibly bind to SARS-CoV-2 M(pro). These acrylamide containing molecules were discovered using our covalent DNA-encoded library (DEL) screening platform. Following selection against SARS-CoV-2 M(pro), off-DNA compounds were synthesized and investigated to determine their inhibitory effects, the nature of their binding, and to generate preliminary structure-activity relationships. LC-MS analysis indicates a 1:1 (covalent) binding stoichiometry between our hit molecules and SARS-CoV-2 M(pro). Fluorescent staining assay for covalent binding in the presence of cell lysate suggests reasonable selectivity for SARS-CoV-2 M(pro). And lastly, inhibition of enzymatic activity was also observed against a panel of 3CLpro enzymes from different coronavirus strains, with IC(50) values ranging from inactive to single digit micromolar. Our results indicate that DEL selection is a useful approach for identifying covalent inhibitors of cysteine proteases.
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spelling pubmed-87679722022-01-19 Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection Ge, Rui Shen, Zuyuan Yin, Jian Chen, Wenhua Zhang, Qi An, Yulong Tang, Dewei Satz, Alexander L. Su, Wenji Kuai, Letian SLAS Discov Full Length Article Covalent inhibitors targeting the main protease (M(pro), or 3CLpro) of SARS-CoV-2 have shown promise in preclinical investigations. Herein, we report the discovery of two new series of molecules that irreversibly bind to SARS-CoV-2 M(pro). These acrylamide containing molecules were discovered using our covalent DNA-encoded library (DEL) screening platform. Following selection against SARS-CoV-2 M(pro), off-DNA compounds were synthesized and investigated to determine their inhibitory effects, the nature of their binding, and to generate preliminary structure-activity relationships. LC-MS analysis indicates a 1:1 (covalent) binding stoichiometry between our hit molecules and SARS-CoV-2 M(pro). Fluorescent staining assay for covalent binding in the presence of cell lysate suggests reasonable selectivity for SARS-CoV-2 M(pro). And lastly, inhibition of enzymatic activity was also observed against a panel of 3CLpro enzymes from different coronavirus strains, with IC(50) values ranging from inactive to single digit micromolar. Our results indicate that DEL selection is a useful approach for identifying covalent inhibitors of cysteine proteases. The Author(s). Published by Elsevier Inc. on behalf of Society for Laboratory Automation and Screening. 2022-03 2022-01-19 /pmc/articles/PMC8767972/ /pubmed/35063690 http://dx.doi.org/10.1016/j.slasd.2022.01.001 Text en © 2022 The Author(s). Published by Elsevier Inc. on behalf of Society for Laboratory Automation and Screening. 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 Full Length Article
Ge, Rui
Shen, Zuyuan
Yin, Jian
Chen, Wenhua
Zhang, Qi
An, Yulong
Tang, Dewei
Satz, Alexander L.
Su, Wenji
Kuai, Letian
Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection
title Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection
title_full Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection
title_fullStr Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection
title_full_unstemmed Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection
title_short Discovery of SARS-CoV-2 main protease covalent inhibitors from a DNA-encoded library selection
title_sort discovery of sars-cov-2 main protease covalent inhibitors from a dna-encoded library selection
topic Full Length Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8767972/
https://www.ncbi.nlm.nih.gov/pubmed/35063690
http://dx.doi.org/10.1016/j.slasd.2022.01.001
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