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
Year of first publication:	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
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-412
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	Molecules 25 9
Pages or article number:	Art. 2064
Publisher:	MDPI
Publisher place:	Basel
Issue date:	2020
ISSN:	1420-3049
Publisher URL:	http://dx.doi.org/10.3390/molecules25092064
Publisher DOI:	10.3390/molecules25092064
Appears in collections:	JGU-Publikationen