E-64c-Hydrazide Based Cathepsin C Inhibitors: Optimizing the Interactions with the S1'-S2' Area.

Autor: Tromsdorf N; Fakultät für Chemie, Hochschule Aalen, Beethovenstraße 1, 73430, Aalen, Germany., Ullrich FTH; Institut für Didaktik und Ausbildungsforschung in der Medizin und Institut für Laboratoriumsmedizin, LMU Klinikum, LMU München, Pettenkoferstraße 8a, 80336, München, Germany., Rethmeier M; Fakultät für Chemie, Universität Bielefeld, Universitätsstraße 25, 33615, Bielefeld, Germany., Sommerhoff CP; Institut für Didaktik und Ausbildungsforschung in der Medizin und Institut für Laboratoriumsmedizin, LMU Klinikum, LMU München, Pettenkoferstraße 8a, 80336, München, Germany., Schaschke N; Fakultät für Chemie, Hochschule Aalen, Beethovenstraße 1, 73430, Aalen, Germany.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2023 Sep 15; Vol. 18 (18), pp. e202300218. Date of Electronic Publication: 2023 Jul 24.
DOI: 10.1002/cmdc.202300218
Abstrakt: The zymogens of the neutrophil serine proteases elastase, proteinase 3, and cathepsin G are converted proteolytically into their pro-inflammatory active forms by the action of cathepsin C. The inhibition of this cysteine protease therefore is an interesting therapeutic approach for the treatment of inflammatory disorders with a high neutrophil burden such as COPD. Based on E-64c-hydrazide as lead structure, we have recently developed a covalently acting cathepsin C inhibitor using a n-butyl residue attached at the amine nitrogen of the hydrazide moiety to efficiently address the deep hydrophobic S2 pocket. To further optimize the affinity and selectivity profile of this inhibitor, the S1'-S2' area was now investigated by a combinatorial approach, showing that Nle-tryptamide is a ligand superior to the initially used Leu-isoamylamide. Using the neutrophil precursor line U937 as a cell culture model, this optimized inhibitor blocks the intracellular cathepsin C activity and thereby suppresses the activation of neutrophil elastase.
(© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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