Cited by 21SARS-CoV-2 and COVID-19 ResearchComputational Drug Discovery MethodsCOVID-19 Clinical Research Studies

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

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Tan, Haozhou, Ma, Chunlong, Wang, Jun·2022·Medicinal Chemistry Research

Abstract

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. Graphical abstract.

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Authors
Tan, H., Ma, C., & Wang, J.
Affiliations
  • Rutgers, The State University of New Jersey (US)
  • University of Arizona (US)
Corresponding author
Wang, Jun
Venue
Medicinal Chemistry Research
Published
2022-05-12
Volume
31
Issue
7
Pages
1147-1153
ISSN
  • 1054-2523 (ISSN-L)
  • 1554-8120
OpenAlex
W4280488476
Cited by
21
References
37
Citations by year
2026: 2 · 2025: 4 · 2024: 5 · 2023: 10
FWCI
2.32
Type
journal article
Language
en
Open access
Locations
  • Medicinal Chemistry Research (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Funders
National Institute of Allergy and Infectious Diseases (AI147325, AI157046, AI158775)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Keywords
dieckol, main protease, papain-like protease, PLpro inhibitors, Mpro inhibitors, antiviral drug repurposing, polyphenols, hit validation, cytotoxicity, ebselen, disulfiram, carmofur, tideglusib, thermal shift assay

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