%0 Electronic Article
%A Srinivasan, Vasundara
%A Brognaro, Hévila
%A Prabhu, Prince R.
%A de Souza, Edmarcia Elisa
%A Günther, Sebastian
%A Reinke, Patrick Y. A.
%A Lane, Thomas J.
%A Ginn, Helen
%A Han, Huijong
%A Ewert, Wiebke
%A Sprenger, Janina
%A Koua, Faisal H. M.
%A Falke, Sven
%A Werner, Nadine
%A Andaleeb, Hina
%A Ullah, Najeeb
%A Franca, Bruno Alves
%A Wang, Mengying
%A Barra, Angélica Luana C
%A Perbandt, Markus
%A Schwinzer, Martin
%A Schmidt, Christina
%A Brings, Lea
%A Lorenzen, Kristina
%A Schubert, Robin
%A Guaragna Machado, Rafael Rahal
%A Candido, Erika Donizette
%A Leal Oliveira, Danielle Bruna
%A Durigon, Edison Luiz
%A Yefanov, Oleksandr
%A Lieske, Julia
%A Gelisio, Luca
%A Domaracky, Martin
%A Middendorf, Philipp
%A Groessler, Michael
%A Trost, Fabian
%A Galchenkova, Marina
%A Saouane, Sofiane
%A Hakanpää, Johanna
%A Wolf, Markus
%A Turk, Dusan
%A Pearson, Arwen R.
%A Chapman, Henry N.
%A Hinrichs, Winfried
%A Wrenger, Carsten
%A Meents, Alke
%A Betzel, Christian
%T SARS-CoV-2 papain-like protease PLpro in complex with natural compounds reveal allosteric sites for antiviral drug design
%M PUBDB-2022-03779
%D 2021
%X 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. 
%F PUB:(DE-HGF)25
%9 Preprint
%R 10.1101/2021.11.17.468943
%U https://bib-pubdb1.desy.de/record/480474