TY  - EJOUR
AU  - Srinivasan, Vasundara
AU  - Brognaro, Hévila
AU  - Prabhu, Prince R.
AU  - de Souza, Edmarcia Elisa
AU  - Günther, Sebastian
AU  - Reinke, Patrick Y. A.
AU  - Lane, Thomas J.
AU  - Ginn, Helen
AU  - Han, Huijong
AU  - Ewert, Wiebke
AU  - Sprenger, Janina
AU  - Koua, Faisal H. M.
AU  - Falke, Sven
AU  - Werner, Nadine
AU  - Andaleeb, Hina
AU  - Ullah, Najeeb
AU  - Franca, Bruno Alves
AU  - Wang, Mengying
AU  - Barra, Angélica Luana C
AU  - Perbandt, Markus
AU  - Schwinzer, Martin
AU  - Schmidt, Christina
AU  - Brings, Lea
AU  - Lorenzen, Kristina
AU  - Schubert, Robin
AU  - Guaragna Machado, Rafael Rahal
AU  - Candido, Erika Donizette
AU  - Leal Oliveira, Danielle Bruna
AU  - Durigon, Edison Luiz
AU  - Yefanov, Oleksandr
AU  - Lieske, Julia
AU  - Gelisio, Luca
AU  - Domaracky, Martin
AU  - Middendorf, Philipp
AU  - Groessler, Michael
AU  - Trost, Fabian
AU  - Galchenkova, Marina
AU  - Saouane, Sofiane
AU  - Hakanpää, Johanna
AU  - Wolf, Markus
AU  - Turk, Dusan
AU  - Pearson, Arwen R.
AU  - Chapman, Henry N.
AU  - Hinrichs, Winfried
AU  - Wrenger, Carsten
AU  - Meents, Alke
AU  - Betzel, Christian
TI  - SARS-CoV-2 papain-like protease PLpro in complex with natural compounds reveal allosteric sites for antiviral drug design
M1  - PUBDB-2022-03779
PY  - 2021
AB  - 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. 
LB  - PUB:(DE-HGF)25
DO  - DOI:10.1101/2021.11.17.468943
UR  - https://bib-pubdb1.desy.de/record/480474
ER  -