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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer US
2022
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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] |
format | Online Article Text |
id | pubmed-9095416 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
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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