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SARS-COV-2 Coronavirus Papain-like Protease PLpro as an Antiviral Target for Inhibitors of Active Site and Protein–Protein Interactions

The papain-like protease PLpro of the SARS-CoV-2 coronavirus is a multifunctional enzyme that catalyzes the proteolytic processing of two viral polyproteins, pp1a and pp1ab. PLpro also cleaves peptide bonds between host cell proteins and ubiquitin (or ubiquitin-like proteins), which is associated wi...

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Detalles Bibliográficos
Autores principales: Ershov, P. V., Yablokov, E. O., Mezentsev, Y. V., Chuev, G. N., Fedotova, M. V., Kruchinin, S. E., Ivanov, A. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Pleiades Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984130/
https://www.ncbi.nlm.nih.gov/pubmed/36883182
http://dx.doi.org/10.1134/S0006350922060082
Descripción
Sumario:The papain-like protease PLpro of the SARS-CoV-2 coronavirus is a multifunctional enzyme that catalyzes the proteolytic processing of two viral polyproteins, pp1a and pp1ab. PLpro also cleaves peptide bonds between host cell proteins and ubiquitin (or ubiquitin-like proteins), which is associated with a violation of immune processes. Nine structures of the most effective inhibitors of the PLpro active center were prioritized according to the parameters of biochemical (IC(50)) and cellular tests to assess the suppression of viral replication (EC(50)) and cytotoxicity (CC(50)). A literature search has shown that PLpro can interact with at least 60 potential protein partners in cells, 23 of which are targets for other viral proteins (human papillomavirus and Epstein-Barr virus). The analysis of protein–protein interactions showed that the proteins USP3, UBE2J1, RCHY1, and FAF2 involved in deubiquitinylation and ubiquitinylation processes contain the largest number of bonds with other proteins; the interaction of viral proteins with them can affect the architecture of the entire network of protein–protein interactions. Using the example of a spatial model of the PLpro/ubiquitin complex and a set of 154 naturally occurring compounds with known antiviral activity, 13 compounds (molecular masses in the range of 454–954 Da) were predicted as potential PLpro inhibitors. These compounds bind to the “hot” amino acid residues of the protease at the positions Gly163, Asp164, Arg166, Glu167, and Tyr264 involved in the interaction with ubiquitin. Thus, pharmacological effects on peripheral PLpro sites, which play important roles in binding protein substrates, may be an additional target-oriented antiviral strategy.