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Iskalni niz: "ključne besede" (papain-like protease) .

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1.
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
Maria Kuzikov, Stefano Morasso, Jeanette Reinshagen, Markus Wolf, Vittoria Monaco, Flora Cozzolino, Simona Golič Grdadolnik, Primož Šket, Janez Plavec, Daniela Iaconis, 2025, izvirni znanstveni članek

Povzetek: 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.
Ključne besede: SARS-CoV-2, drug repurposing, papain-like protease, redox, STD-NMR, CPI-169, GRL-0617
Objavljeno v DiRROS: 20.08.2025; Ogledov: 279; Prenosov: 132
.pdf Celotno besedilo (1,73 MB)
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2.
Identification of triazolopyrimidinyl scaffold SARS-CoV-2 papain-like protease (PLpro) inhibitor
Sebastjan Kralj, Marko Jukič, Miha Bahun, Luka Kranjc, Anja Kolarič, Milan Hodošček, Nataša Poklar Ulrih, Urban Bren, 2024, izvirni znanstveni članek

Povzetek: The global impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its companion disease, COVID-19, has reminded us of the importance of basic coronaviral research. In this study, a comprehensive approach using molecular docking, in vitro assays, and molecular dynamics simulations was applied to identify potential inhibitors for SARS-CoV-2 papain-like protease (PLpro), a key and underexplored viral enzyme target. A focused protease inhibitor library was initially created and molecular docking was performed using CmDock software (v0.2.0), resulting in the selection of hit compounds for in vitro testing on the isolated enzyme. Among them, compound 372 exhibited promising inhibitory properties against PLpro, with an IC50 value of 82 ± 34 μM. The compound also displayed a new triazolopyrimidinyl scaffold not yet represented within protease inhibitors. Molecular dynamics simulations demonstrated the favorable binding properties of compound 372. Structural analysis highlighted its key interactions with PLpro, and we stress its potential for further optimization. Moreover, besides compound 372 as a candidate for PLpro inhibitor development, this study elaborates on the PLpro binding site dynamics and provides a valuable contribution for further efforts in pan-coronaviral PLpro inhibitor development.
Ključne besede: drug design, protease inhibitor, SARS-CoV-2, papain-like protease, PLpro, antiviral design, in silico drug design, CADD, virtual screening, HTVS, structure-based design
Objavljeno v DiRROS: 07.08.2024; Ogledov: 863; Prenosov: 716
.pdf Celotno besedilo (6,86 MB)
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