Author: Rungrotmongkol, Thanyada ; Darai, Nitchakan ; Rajchakom, Chananya ; Nualkaew, Somsak ; Sripadung, Ployvadee ; Puthongking, Ploenthip ; Sungthong, Bunleu ; Boonma, Thitiya ; Nunthaboot, Nadtanet

Abstract: Over 5 years, COVID-19 has spread globally, causing 774 million cases and 7 million deaths.Challenges such as ineffective treatments, vaccine hesitancy, gene mutations, and high drug costs highlight the need for new inhibitors.SARS-CoV-2′s papain-like protease (PLpro), crucial for viral replication, is a promising target for treatment.This study used structure-based virtual screening, pharmacokinetic anal., mol. docking, and mol. dynamics (MD) simulation to identify phytochem. inhibitors of PLpro.From 45 Thai medicinal plant-derived phytochems., 27 compounds met Lipinski′s rule of 5 criteria and underwent ADMET and mol. docking anal.The top 15% of compounds with the highest docking scores, (3R)-7,4′-dihydroxy-8-methoxyhomoisoflavane, bergenin, capparispine, and feruloyl tyramine, were subjected to 100 ns MD simulations to assess their stability and interactions with SARS-CoV-2 PLpro.Compounds (3R)-7,4′-dihydroxy-8-methoxyhomoisoflavane, bergenin, and capparispine showed extensive interactions with key PLpro residues, including D164, R166, P247, P248, Y264, Y268, Y273 Q269, and D302 through hydrogen bonding and hydrophobic interactions.In contrast, feruloyl tyramine exhibited weaker interaction, forming only non-polar contacts with PLpro residues P247, P248, Y264, and Y268.MM/GBSA anal. confirmed strong and favorable binding energies for (3R)-7,4′-dihydroxy-8-methoxyhomoisoflavane, bergenin, and capparispine, suggesting their potential as PLpro inhibitors.This information could contribute in the developing of effective SARS-CoV-2 inhibitors.Graphical abstract:

01 Feb 2025·Journal of Molecular Structure

Integrated computational and experimental approaches to identify new papain-like protease inhibitors

Author: Singh, Rahul ; Chauhan, Mahima ; Kumar, Arun ; Dhiman, Anurag ; Anurag ; Purohit, Rituraj

SARS-CoV-2 papain-like protease (PLpro), a key viral protease, plays a crucial role in the viral replication and pathogenesis, making it an attractive target for the development of antiviral therapies.Thus to target PLpro, the chlorogenic acid was chosen based on its well-established characteristics as a natural compound with inhibitory properties against viral proteases.The research strategy involved a synergistic combination of in-silico and in-vitro techniques, enabled successful identification of a natural inhibitor for PLpro.In the docking anal., it was observed that chlorogenic acid exhibited a more pronounced interaction energy with PLpro compared to GRL0617.Addnl., the mol. dynamics simulations demonstrated remarkable stability of the chlorogenic acid-PLpro complex, along with close proximity in conformational dynamics.The assessment of post-processing end-state free energies indicated comparable affinities for both mols.Furthermore, the enzymic inhibition assay performed for dose-response anal. provided validation for chlorogenic acid as a potential inhibitor of PLpro.This exptl. assessment strengthens the evidence supporting the inhibitory activity of chlorogenic acid against PLpro.Overall, this comprehensive anal. serves as a valuable platform for the development of potential therapeutic candidates targeting PLpro, offering promising prospects for combating SARS-CoV-2.

10 Jan 2025·ACS Pharmacology & Translational Science

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

Article

Author: Beccari, Andrea R. ; Reinshagen, Jeanette ; Gribbon, Philip ; Monti, Maria ; Cozzolino, Flora ; Corona, Angela ; Iaconis, Daniela ; Summa, Vincenzo ; Paulis, Annalaura ; Storici, Paola ; Manelfi, Candida ; Golič Grdadolnik, Simona ; Monaco, Vittoria ; Zaliani, Andrea ; Plavec, Janez ; Šket, Primož ; Esposito, Francesca ; Windshügel, Björn ; Kuzikov, Maria ; Wolf, Markus ; Morasso, Stefano ; Tramontano, Enzo

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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Indication	Highest Phase	Country/Location	Organization	Date
COVID-19	Preclinical	Germany	Max Planck Institute of Biophysics	29 Jul 2020
COVID-19	Preclinical	-	Johann Wolfgang Goethe-Universität Frankfurt am Main	29 Jul 2020
Severe Acute Respiratory Syndrome	Preclinical	United States	University of Illinois	21 Oct 2008

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