Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-401
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 |
Year of first publication: | 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 |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-401 |
URN: | urn:nbn:de:hebis:77-publ-598260 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/4.0/ |
Journal: | Molecules 25 6 |
Pages or article number: | Art. 1451 |
Publisher: | MDPI |
Publisher place: | Basel |
Issue date: | 2020 |
ISSN: | 1420-3049 |
Publisher URL: | http://dx.doi.org/10.3390/molecules25061451 |
Publisher DOI: | 10.3390/molecules25061451 |
Appears in collections: | JGU-Publikationen |