| Autor: |
Arwen R. Pearson, N. Ullah, Christian Betzel, M. Groessler, M. Galchenkova, Huijong Han, Winfried Hinrichs, Sebastian Guenther, Philipp Middendorf, Sven Falke, Hévila Brognaro, Markus Perbandt, L. Brings, Janina Sprenger, J. Lieske, Angelica Luana C Barra, Rafael Rahal Guaragna Machado, Kristina Lorenzen, Faisal H. M. Koua, Carsten Wrenger, Thomas J. Lane, Vasundara Srinivasan, Edmarci Elisa de Souza, Bruno Alves Franca, Patrick Y. A. Reinke, Alke Meents, J. Hakanpaeae, Prince Rajaiah Prabhu, M. Domaracky, Edison Luiz Durigon, Oleksandr Yefanov, F. Trost, Dušan Turk, H. Andaleeb, Danielle Bruna Leal Oliveira, Markus Wolf, M. Wang, Helen M. Ginn, Robin Schubert, W. Ewert, M. Schwinzer, N. Werner, C. Schmidt, Sofiane Saouane, Henry N. Chapman, Erika Donizette Candido, Luca Gelisio |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
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 host’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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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