| Title: | Thiol-reactive or redox-active : revising a repurposing screen led to a new invalidation pipeline and identified a true noncovalent inhibitor against papain-like protease from SARS-CoV-2 |
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| Authors: | ID Kuzikov, Maria (Author)
ID Morasso, Stefano (Author)
ID Reinshagen, Jeanette (Author)
ID Wolf, Markus (Author)
ID Monaco, Vittoria (Author)
ID Cozzolino, Flora (Author)
ID Golič Grdadolnik, Simona (Author)
ID Šket, Primož (Author)
ID Plavec, Janez (Author)
ID Iaconis, Daniela (Author) |
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| Files: |  URL - Source URL, visit https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00325
 PDF - Presentation file, download (1,73 MB)
MD5: CFFE6BC29B0ECC881928D89D786DC1EB
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| Language: | English |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: |  KI - National Institute of Chemistry
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| Abstract: | The SARS-CoV-2 papain-like protease PLpro has multiple roles in the viral replication cycle, related to both its polypeptide cleavage function and its ability to antagonize the host immune response. Targeting the PLpro function is recognized as a promising mechanism to modulate viral replication, while supporting host immune responses. However, the development of PLpro-specific inhibitors remains challenging. Comprehensive investigations utilizing enzymatic, binding studies, and cellular assays revealed the previously reported inhibitors to act in an unspecific manner. At present, GRL-0617 and its derivatives remain the best-validated compounds with demonstrated antiviral activity in cells and in mouse models. In this study, we refer to the pitfalls of the redox sensitivity of PLpro. Using a screening-based approach to identify inhibitors of PLpro’s proteolytic activity, we made extensive efforts to validate active compounds over a range of conditions and readouts, emphasizing the need for comprehensive orthogonal data when profiling putative PLpro inhibitors. The remaining active compound, CPI-169, was shown to be a noncovalent inhibitor capable of competing with GRL-0617 in NMR-based experiments, suggesting that it occupied a similar binding site and inhibited viral replication in Vero-E6 cells, opening new design opportunities for further development as antiviral agents. |
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| Keywords: | SARS-CoV-2, drug repurposing, papain-like protease, redox, STD-NMR, CPI-169, GRL-0617 |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Publication date: | 10.01.2025 |
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| Year of publishing: | 2025 |
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| Number of pages: | str. 66–77 |
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| Numbering: | Vol. 8, iss. 1 |
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| PID: | 20.500.12556/DiRROS-23338  |
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| UDC: | 577 |
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| ISSN on article: | 2575-9108 |
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| DOI: | 10.1021/acsptsci.4c00325 |
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| COBISS.SI-ID: | 213383683 |
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| Copyright: | © 2024 The Authors. Published by American Chemical Society |
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| Note: | Nasl. z nasl. zaslona;
Opis vira z dne 10. 1. 2025;
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| Publication date in DiRROS: | 20.08.2025 |
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| Views: | 330 |
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| Downloads: | 160 |
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