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Authors: Klein, Philipp
Johe, Patrick
Wagner, Annika
Jung, Sascha
Kühlborn, Jonas
Barthels, Fabian
Tenzer, Stefan
Distler, Ute
Waigel, Waldemar
Engels, Bernd
Hellmich, Ute
Opatz, Till
Schirmeister, Tanja
Title: New cysteine protease inhibitors : electrophilic (het)arenes and unexpected prodrug identification for the trypanosoma protease rhodesain
Online publication date: 18-May-2020
Language: english
Abstract: Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the SNAr addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of a peptidic recognition sequence with such electrophilic (het)arenes to generate highly active inhibitors of disease-relevant proteases. We further elucidate an unexpected mode of action for the trypanosomal protease rhodesain using NMR spectroscopy and mass spectrometry, enzyme kinetics and various types of simulations. After hydrolysis of an ester function in the recognition sequence of a weakly active prodrug inhibitor, the liberated carboxylic acid represents a highly potent inhibitor of rhodesain (Ki = 4.0 nM). The simulations indicate that, after the cleavage of the ester, the carboxylic acid leaves the active site and re-binds to the enzyme in an orientation that allows the formation of a very stable π-complex between the catalytic dyad (Cys-25/His-162) of rhodesain and the electrophilic aromatic moiety. The reversible inhibition mode results because the SNAr reaction, which is found in an alkaline solvent containing a low molecular weight thiol, is hindered within the enzyme due to the presence of the positively charged imidazolium ring of His-162. Comparisons between measured and calculated NMR shifts support this interpretation.
DDC: 570 Biowissenschaften
570 Life sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 09 Chemie, Pharmazie u. Geowissensch.
FB 04 Medizin
Place: Mainz
URN: urn:nbn:de:hebis:77-publ-598260
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: Molecules
Pages or article number: Art. 1451
Publisher: MDPI
Publisher place: Basel
Issue date: 2020
ISSN: 1420-3049
Publisher URL:
Publisher DOI: 10.3390/molecules25061451
Appears in collections:JGU-Publikationen

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