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Authors: Klein, Philipp
Barthels, Fabian
Johe, Patrick
Wagner, Annika
Tenzer, Stefan
Distler, Ute
Le, Thien Anh
Schmid, Paul
Engel, Volker
Engels, Bernd
Hellmich, Ute
Opatz, Till
Schirmeister, Tanja
Title: Naphthoquinones as covalent reversible inhibitors of cysteine proteases : studies on inhibition mechanism and kinetics
Online publication date: 23-Jun-2020
Language: english
Abstract: The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.
DDC: 570 Biowissenschaften
570 Life sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
FB 09 Chemie, Pharmazie u. Geowissensch.
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: Molecules
Pages or article number: Art. 2064
Publisher: MDPI
Publisher place: Basel
Issue date: 2020
ISSN: 1420-3049
Publisher URL:
Publisher DOI: 10.3390/molecules25092064
Appears in collections:JGU-Publikationen

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