Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease

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Srinivasan, Vasundara ; Brognaro, Hevila ; Prabhu, Prince R. ; de Souza, Edmarcia Elisa ; Guenther, Sebastian ; Reinke, Patrick Y. A. ; Lane, Thomas J. ; Ginn, Helen ; Han, Huijong ; Ewert, Wiebke ; Sprenger, Janina ; Koua, Faisal H. M. ; Falke, Sven ; Werner, Nadine ; Andaleeb, Hina ; Ullah, Najeeb ; Franca, Bruno Alves ; Wang, Mengying ; Barra, Angelica Luana C. ; Perbandt, Markus ; Schwinzer, Martin ; Schmidt, Christina ; Brings, Lea ; Lorenzen, Kristina ; Schubert, Robin ; Guaragna Machado, Rafael Rahal ; Candido, Erika Donizette ; Leal Oliveira, Danielle Bruna ; Durigon, Edison Luiz ; Niebling, Stephan ; Garcia, Angelica Struve ; Yefanov, Oleksandr ; Lieske, Julia ; Gelisio, Luca ; Domaracky, Martin ; Middendorf, Philipp ; Groessler, Michael ; Trost, Fabian ; Galchenkova, Marina ; Mashhour, Aida Rahmani ; Saouane, Sofiane ; Hakanpaeae, Johanna ; Wolf, Markus ; Alai, Maria Garcia ; Turk, Dusan ; Pearson, Arwen R. ; Chapman, Henry N. ; Hinrichs, Winfried ; Wrenger, Carsten ; Meents, Alke ; Betzel, Christian

• Document type: Journal article
• Source: COMMUNICATIONS BIOLOGY; v. 5, n. 1, p. 12-pg., 2022-08-11.

Abstract

Three natural phenolic compounds are found to bind to an allosteric site in SARS-CoV-2 papain-like protease and exhibit antiviral activity in vitro, showing potential as starting scaffolds for drug design. SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host's innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections. (AU)

• FAPESP's process: 15/26722-8 - Drug discovery against human infectious diseases
• Grantee: Carsten Wrenger
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/00899-0 - Structural dissection of nanoparticle-assisted drug delivery in human infectious diseases
• Grantee: Carsten Wrenger
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/12277-0 - Drug discovery against human infectious diseases
• Grantee: Edmarcia Elisa de Souza
• Support Opportunities: Scholarships in Brazil - Post-Doctoral