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Abstract of [Srinivasan21]

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SARS-CoV-2 papain-like protease PLpro in complex with natural compounds reveal allosteric sites for antiviral drug design

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

(preprint, 2021)


SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to aid coronaviruses in evading the hostí»s innate immune responses. We established a high-throughput X-ray screening to identify inhibitors by elucidating the native PLpro structure refined to 1.42 Å and performing co-crystallization utilizing a diverse library of selected natural compounds. We identified three phenolic compounds as potential inhibitors. Crystal structures of PLpro inhibitor complexes, obtained to resolutions between 1.7-1.9 Å, show that all three compounds bind at the ISG15/Ub-S2 allosteric binding site, preventing the essential ISG15-PLpro molecular interactions. All compounds demonstrate clear inhibition in a deISGylation assay, two exhibit distinct antiviral activity and one inhibited a cytopathic effect in a non-cytotoxic concentration range. These results highlight the druggability of the rarely explored ISG15/Ub-S2 PLpro allosteric binding site to identify new and effective antiviral compounds. Importantly, 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.

Tags: corona, covid, XBI, European XFEL

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