TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Ewert, Wiebke
A1  - Günther, Sebastian
A1  - Miglioli, Francesca
A1  - Falke, Sven
A1  - Reinke, Patrick Y. A.
A1  - Niebling, Stephan
A1  - Günther, Christian
A1  - Han, Huijong
A1  - Srinivasan, Vasundara
A1  - Brognaro, Hévila
A1  - Lieske, Julia
A1  - Lorenzen, Kristina
A1  - Garcia-Alai, Maria M.
A1  - Betzel, Christian
A1  - Carcelli, Mauro
A1  - Hinrichs, Winfried
A1  - Rogolino, Dominga
A1  - Meents, Alke
T1  - Hydrazones and Thiosemicarbazones Targeting Protein-Protein-Interactions of SARS-CoV-2 Papain-like Protease
JF  - Frontiers in Chemistry
N2  - 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.
KW  - -
KW  - drug discovery
KW  - COVID-19
KW  - papain-like protease
KW  - x-ray crystallography
KW  - deubiquitination
KW  - SARS-CoV-2
KW  - lead compounds
UN  - https://nbn-resolving.org/urn:nbn:de:gbv:9-opus-61734
SN  - 2296-2646
SS  - 2296-2646
U6  - https://doi.org/10.3389/fchem.2022.832431
DO  - https://doi.org/10.3389/fchem.2022.832431
VL  - 10
PB  - Frontiers Media S.A.
CY  - 13
ER  -