Invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) as SARS-CoV-2 main protease inhibitors and the discovery of PGG as a papain-like protease inhibitor

The COVID-19 pandemic spurred a broad interest in antiviral drug discovery. The SARS-CoV-2 main protease (M(pro)) and papain-like protease (PL(pro)) are attractive antiviral drug targets given their vital roles in viral replication and modulation of host immune response. Structurally disparate compo...

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Autores principales: Tan, Haozhou, Ma, Chunlong, Wang, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095416/
https://www.ncbi.nlm.nih.gov/pubmed/35578732
http://dx.doi.org/10.1007/s00044-022-02903-0
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author Tan, Haozhou
Ma, Chunlong
Wang, Jun
author_facet Tan, Haozhou
Ma, Chunlong
Wang, Jun
author_sort Tan, Haozhou
collection PubMed
description The COVID-19 pandemic spurred a broad interest in antiviral drug discovery. The SARS-CoV-2 main protease (M(pro)) and papain-like protease (PL(pro)) are attractive antiviral drug targets given their vital roles in viral replication and modulation of host immune response. Structurally disparate compounds were reported as M(pro) and PL(pro) inhibitors from either drug repurposing or rational design. Two polyphenols dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) were recently reported as SARS-CoV-2 M(pro) inhibitors. With our continuous interest in studying the mechanism of inhibition and resistance of M(pro) inhibitors, we report herein our independent validation/invalidation of these two natural products. Our FRET-based enzymatic assay showed that neither dieckol nor PGG inhibited SARS-CoV-2 M(pro) (IC(50) > 20 µM), which is in contrary to previous reports. Serendipitously, PGG was found to inhibit the SARS-CoV-2 PL(pro) with an IC(50) of 3.90 µM. The binding of PGG to PL(pro) was further confirmed in the thermal shift assay. However, PGG was cytotoxic in 293T-ACE2 cells (CC(50) = 7.7 µM), so its intracellular PL(pro) inhibitory activity could not be quantified by the cell-based Flip-GFP PL(pro) assay. In addition, we also invalidated ebselen, disulfiram, carmofur, PX12, and tideglusib as SARS-CoV-2 PL(pro) inhibitors using the Flip-GFP assay. Overall, our results call for stringent hit validation, and the serendipitous discovery of PGG as a putative PL(pro) inhibitor might worth further pursuing. [Figure: see text]
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spelling pubmed-90954162022-05-12 Invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) as SARS-CoV-2 main protease inhibitors and the discovery of PGG as a papain-like protease inhibitor Tan, Haozhou Ma, Chunlong Wang, Jun Med Chem Res Original Research The COVID-19 pandemic spurred a broad interest in antiviral drug discovery. The SARS-CoV-2 main protease (M(pro)) and papain-like protease (PL(pro)) are attractive antiviral drug targets given their vital roles in viral replication and modulation of host immune response. Structurally disparate compounds were reported as M(pro) and PL(pro) inhibitors from either drug repurposing or rational design. Two polyphenols dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) were recently reported as SARS-CoV-2 M(pro) inhibitors. With our continuous interest in studying the mechanism of inhibition and resistance of M(pro) inhibitors, we report herein our independent validation/invalidation of these two natural products. Our FRET-based enzymatic assay showed that neither dieckol nor PGG inhibited SARS-CoV-2 M(pro) (IC(50) > 20 µM), which is in contrary to previous reports. Serendipitously, PGG was found to inhibit the SARS-CoV-2 PL(pro) with an IC(50) of 3.90 µM. The binding of PGG to PL(pro) was further confirmed in the thermal shift assay. However, PGG was cytotoxic in 293T-ACE2 cells (CC(50) = 7.7 µM), so its intracellular PL(pro) inhibitory activity could not be quantified by the cell-based Flip-GFP PL(pro) assay. In addition, we also invalidated ebselen, disulfiram, carmofur, PX12, and tideglusib as SARS-CoV-2 PL(pro) inhibitors using the Flip-GFP assay. Overall, our results call for stringent hit validation, and the serendipitous discovery of PGG as a putative PL(pro) inhibitor might worth further pursuing. [Figure: see text] Springer US 2022-05-12 2022 /pmc/articles/PMC9095416/ /pubmed/35578732 http://dx.doi.org/10.1007/s00044-022-02903-0 Text en © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Original Research
Tan, Haozhou
Ma, Chunlong
Wang, Jun
Invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) as SARS-CoV-2 main protease inhibitors and the discovery of PGG as a papain-like protease inhibitor
title Invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) as SARS-CoV-2 main protease inhibitors and the discovery of PGG as a papain-like protease inhibitor
title_full Invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) as SARS-CoV-2 main protease inhibitors and the discovery of PGG as a papain-like protease inhibitor
title_fullStr Invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) as SARS-CoV-2 main protease inhibitors and the discovery of PGG as a papain-like protease inhibitor
title_full_unstemmed Invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) as SARS-CoV-2 main protease inhibitors and the discovery of PGG as a papain-like protease inhibitor
title_short Invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (PGG) as SARS-CoV-2 main protease inhibitors and the discovery of PGG as a papain-like protease inhibitor
title_sort invalidation of dieckol and 1,2,3,4,6-pentagalloylglucose (pgg) as sars-cov-2 main protease inhibitors and the discovery of pgg as a papain-like protease inhibitor
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095416/
https://www.ncbi.nlm.nih.gov/pubmed/35578732
http://dx.doi.org/10.1007/s00044-022-02903-0
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