Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease
Vasundara Srinivasan, H. Brognaro, Prabhu Rajaiah Prince, Edmárcia Elisa de Souza, Sebastian Günther, P. Reinke, Thomas J. Lane, Helen M. Ginn, Huijong Han, Wiebke Ewert, Janina Sprenger, F. Koua, Sven Falke, N. Werner, Hina Andaleeb, Najeeb Ullah, B. Alves Franca, Mengying Wang, Angélica Luana C. Barra, Markus Perbandt, M. Schwinzer, Christina Schmidt, Lea Brings, Kristina Lorenzen, Robin Schubert, Rafael Rahal Guaragna Machado, Erika Donizette Candido, Danielle Bruna Leal Oliveira, Edison Luíz Durigon, Stephan Niebling, Angelica Struve García, Oleksandr Yefanov, J. Lieske, Luca Gelisio, M. Domaracký, Philipp Middendorf, M. Groessler, F. Trost, M. Galchenkova, Aida Rahmani Mashhour, S. Saouane, Johanna Hakanpää, Markus Wolf, María García-Alai, Vito Türk, Arwen R. Pearson, Henry N. Chapman, Winfried Hinrichs, Carsten Wrenger, Alke Meents, Christian Betzel
Abstract
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.