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Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease

  • The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation of the host innate immune system. Using a library of 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome we identified six compounds binding to the target protein. Here we describe the interaction of one hydrazone (H1) and five thiosemicarbazone (T1-T5) compounds with the two distinct natural substrate binding sites of PLpro for ubiquitin and ISG15. H1 binds to a polar groove at the S1 binding site by forming several hydrogen bonds with PLpro. T1-T5 bind into a deep pocket close to the polyubiquitin and ISG15 binding site S2. Their interactions are mainly mediated by multiple hydrogen bonds and further hydrophobic interactions. In particular compound H1 interferes with natural substrate binding by sterical hindrance and induces conformational changes in protein residues involved in substrate binding, while compounds T1-T5 could have a more indirect effect. Fluorescence based enzyme activity assay and complementary thermal stability analysis reveal only weak inhibition properties in the high micromolar range thereby indicating the need for compound optimization. Nevertheless, the unique binding properties involving strong hydrogen bonding and the various options for structural optimization make the compounds ideal lead structures. In combination with the inexpensive and undemanding synthesis, the reported hydrazone and thiosemicarbazones represent an attractive scaffold for further structure-based development of novel PLpro inhibitors by interrupting protein-protein interactions at the S1 and S2 site.

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Metadaten
Author: Wiebke Ewert, Sebastian Günther, Francesca Miglioli, Sven Falke, Patrick Y. A. Reinke, Stephan Niebling, Christian Günther, Huijong Han, Vasundara Srinivasan, Hévila Brognaro, Julia Lieske, Kristina Lorenzen, Maria M. Garcia-Alai, Christian Betzel, Mauro Carcelli, Winfried Hinrichs, Dominga Rogolino, Alke Meents
URN:urn:nbn:de:gbv:9-opus-61734
DOI:https://doi.org/10.3389/fchem.2022.832431
ISSN:2296-2646
Parent Title (English):Frontiers in Chemistry
Publisher:Frontiers Media S.A.
Place of publication:13
Document Type:Article
Language:English
Date of first Publication:2022/04/11
Release Date:2022/11/24
Tag:COVID-19; SARS-CoV-2; deubiquitination; drug discovery; lead compounds; papain-like protease; x-ray crystallography
GND Keyword:-
Volume:10
Article Number:832431
Faculties:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Chemie und Biochemie
Licence (German):License LogoCreative Commons - Namensnennung