Autoren:	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
Titel:	Naphthoquinones as covalent reversible inhibitors of cysteine proteases : studies on inhibition mechanism and kinetics
Online-Publikationsdatum:	23-Jun-2020
Erscheinungsdatum:	2020
Sprache des Dokuments:	Englisch
Zusammenfassung/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-Sachgruppe:	570 Biowissenschaften 570 Life sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin FB 09 Chemie, Pharmazie u. Geowissensch.
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-412
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	Molecules 25 9
Seitenzahl oder Artikelnummer:	Art. 2064
Verlag:	MDPI
Verlagsort:	Basel
Erscheinungsdatum:	2020
ISSN:	1420-3049
URL der Originalveröffentlichung:	http://dx.doi.org/10.3390/molecules25092064
DOI der Originalveröffentlichung:	10.3390/molecules25092064
Enthalten in den Sammlungen:	JGU-Publikationen