TY  - JOUR
A1  - Klein, Philipp
A1  - Barthels, Fabian
A1  - Johe, Patrick
A1  - Wagner, Annika
A1  - Tenzer, Stefan
A1  - Distler, Ute
A1  - Le, Thien Anh
A1  - Schmid, Paul
A1  - Engel, Volker
A1  - Engels, Bernd
A1  - Hellmich, Ute A.
A1  - Opatz, Till
A1  - Schirmeister, Tanja
T1  - Naphthoquinones as covalent reversible inhibitors of cysteine proteases — studies on inhibition mechanism and kinetics
T2  - Molecules
N2  - 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.
KW  - protease
KW  - rhodesain
KW  - covalent reversible inhibition
KW  - 1,4-naphthoquinone
KW  - nucleophilic addition
KW  - prodrug
Y1  - 2020
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/20379
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-203791
SN  - 1420-3049
VL  - 25
IS  - 9
ER  -