New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Philipp Klein
- Patrick Johe
- Annika Wagner
- Sascha Jung
- Jonas Kuehlborn
- Fabian Barthels
- Stefan Tenzer
- Ute Distler
- Waldemar Waigel
- Bernd Engels
- Ute A Hellmich
- Till Opatz
- Tanja Schirmeister
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000530248700194&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.3390/molecules25061451
- eISSN
- 1420-3049
- Externe Identifier
- Clarivate Analytics Document Solution ID: LJ6BO
- PubMed Identifier: 32210166
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- MOLECULES
- Schlüsselwörter
- cysteine protease
- rhodesain
- electrophilic (het)arene
- nucleophilic aromatic substitution
- Meisenheimer complex
- pi-complex
- prodrug
- Artikelnummer
- ARTN 1451
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Titel
- New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the <i>Trypanosoma</i> Protease Rhodesain
- Sub types
- Article
- Ausgabe der Zeitschrift
- 25
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:p>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.</jats:p>
- Autoren
- Philipp Klein
- Patrick Johe
- Annika Wagner
- Sascha Jung
- Jonas Kühlborn
- Fabian Barthels
- Stefan Tenzer
- Ute Distler
- Waldemar Waigel
- Bernd Engels
- Ute A Hellmich
- Till Opatz
- Tanja Schirmeister
- DOI
- 10.3390/molecules25061451
- eISSN
- 1420-3049
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- Molecules
- Sprache
- en
- Online publication date
- 2020
- Paginierung
- 1451 - 1451
- Status
- Published online
- Herausgeber
- MDPI AG
- Herausgeber URL
- http://dx.doi.org/10.3390/molecules25061451
- Datum der Datenerfassung
- 2020
- Titel
- New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain
- Ausgabe der Zeitschrift
- 25
Data source: Crossref
- Abstract
- Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the S<sub>N</sub>Ar 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 (<i>K</i><sub>i</sub> = 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 S<sub>N</sub>Ar 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.
- Addresses
- Department of Chemistry, Organic Chemistry Section, Johannes Gutenberg-Universität, 55128 Mainz, Germany.
- Autoren
- Philipp Klein
- Patrick Johe
- Annika Wagner
- Sascha Jung
- Jonas Kühlborn
- Fabian Barthels
- Stefan Tenzer
- Ute Distler
- Waldemar Waigel
- Bernd Engels
- Ute A Hellmich
- Till Opatz
- Tanja Schirmeister
- DOI
- 10.3390/molecules25061451
- eISSN
- 1420-3049
- Externe Identifier
- PubMed Identifier: 32210166
- PubMed Central ID: PMC7145299
- Funding acknowledgements
- Carl Zeiss Stiftung: ChemBioMed
- Deutsche Forschungsgemeinschaft: INST 161/916-1 FUGG
- Open access
- true
- ISSN
- 1420-3049
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- Molecules (Basel, Switzerland)
- Schlüsselwörter
- Trypanosoma
- Cysteine Endopeptidases
- Protozoan Proteins
- Cysteine Proteinase Inhibitors
- Structure-Activity Relationship
- Sprache
- eng
- Medium
- Electronic
- Online publication date
- 2020
- Open access status
- Open Access
- Paginierung
- E1451
- Datum der Veröffentlichung
- 2020
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2020
- Titel
- New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the <i>Trypanosoma</i> Protease Rhodesain.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 25
Files
https://www.mdpi.com/1420-3049/25/6/1451/pdf?version=1585273627 https://europepmc.org/articles/PMC7145299?pdf=render
Data source: Europe PubMed Central
- 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.
- Date of acceptance
- 2020
- Autoren
- Philipp Klein
- Patrick Johe
- Annika Wagner
- Sascha Jung
- Jonas Kühlborn
- Fabian Barthels
- Stefan Tenzer
- Ute Distler
- Waldemar Waigel
- Bernd Engels
- Ute A Hellmich
- Till Opatz
- Tanja Schirmeister
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/32210166
- DOI
- 10.3390/molecules25061451
- eISSN
- 1420-3049
- Externe Identifier
- PubMed Central ID: PMC7145299
- Funding acknowledgements
- Deutsche Forschungsgemeinschaft: INST 161/916-1 FUGG
- Carl Zeiss Stiftung: ChemBioMed
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- Molecules
- Schlüsselwörter
- Meisenheimer complex
- cysteine protease
- electrophilic (het)arene
- nucleophilic aromatic substitution
- prodrug
- rhodesain
- π-complex
- Cysteine Endopeptidases
- Cysteine Proteinase Inhibitors
- Protozoan Proteins
- Structure-Activity Relationship
- Trypanosoma
- Sprache
- eng
- Country
- Switzerland
- PII
- molecules25061451
- Datum der Veröffentlichung
- 2020
- Status
- Published online
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2020
- Titel
- New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 25
Data source: PubMed
- Author's licence
- CC-BY
- Autoren
- Philipp Klein
- Patrick Johe
- Annika Wagner
- Sascha Jung
- Jonas Kühlborn
- Fabian Barthels
- Stefan Tenzer
- Ute Distler
- Waldemar Waigel
- Bernd Engels
- Ute Hellmich
- Till Opatz
- Tanja Schirmeister
- Hosting institution
- Universitätsbibliothek Mainz
- Sammlungen
- JGU-Publikationen
- Resource version
- Published version
- URN
- urn:nbn:de:hebis:77-publ-598260
- DOI
- 10.3390/molecules25061451
- Funding acknowledgements
- DFG, Open Access-Publizieren Universität Mainz / Universitätsmedizin
- File(s) embargoed
- false
- Open access
- true
- ISSN
- 1420-3049
- Ausgabe der Veröffentlichung
- 6
- Zeitschrift
- Molecules
- Schlüsselwörter
- 570 Biowissenschaften
- 570 Life sciences
- Sprache
- eng
- Open access status
- Open Access
- Paginierung
- Art. 1451
- Datum der Veröffentlichung
- 2020
- Public URL
- https://openscience.ub.uni-mainz.de/handle/20.500.12030/403
- Herausgeber
- MDPI
- Herausgeber URL
- http://dx.doi.org/10.3390/molecules25061451
- Datum der Datenerfassung
- 2020
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2020
- Zugang
- Public
- Titel
- New cysteine protease inhibitors : electrophilic (het)arenes and unexpected prodrug identification for the trypanosoma protease rhodesain
- Ausgabe der Zeitschrift
- 25
Files
59826.pdf
Data source: OPENSCIENCE.UB
- Beziehungen:
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