Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Sascha Jung
- Natalie Fuchs
- Patrick Johe
- Annika Wagner
- Erika Diehl
- Tri Yuliani
- Collin Zimmer
- Fabian Barthels
- Robert A Zimmermann
- Philipp Klein
- Waldemar Waigel
- Jessica Meyr
- Till Opatz
- Stefan Tenzer
- Ute Distler
- Hans-Joachim Raeder
- Christian Kersten
- Bernd Engels
- Ute A Hellmich
- Jochen Klein
- Tanja Schirmeister
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000692012400031&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/acs.jmedchem.1c01002
- eISSN
- 1520-4804
- Externe Identifier
- Clarivate Analytics Document Solution ID: UK5LZ
- PubMed Identifier: 34378914
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 16
- Zeitschrift
- JOURNAL OF MEDICINAL CHEMISTRY
- Paginierung
- 12322 - 12358
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Titel
- Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies
- Sub types
- Article
- Ausgabe der Zeitschrift
- 64
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Autoren
- Sascha Jung
- Natalie Fuchs
- Patrick Johe
- Annika Wagner
- Erika Diehl
- Tri Yuliani
- Collin Zimmer
- Fabian Barthels
- Robert A Zimmermann
- Philipp Klein
- Waldemar Waigel
- Jessica Meyr
- Till Opatz
- Stefan Tenzer
- Ute Distler
- Hans-Joachim Räder
- Christian Kersten
- Bernd Engels
- Ute A Hellmich
- Jochen Klein
- Tanja Schirmeister
- DOI
- 10.1021/acs.jmedchem.1c01002
- eISSN
- 1520-4804
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 16
- Zeitschrift
- Journal of Medicinal Chemistry
- Sprache
- en
- Online publication date
- 2021
- Paginierung
- 12322 - 12358
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/acs.jmedchem.1c01002
- Datum der Datenerfassung
- 2023
- Titel
- Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure–Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies
- Ausgabe der Zeitschrift
- 64
Datenquelle: Crossref
- Abstract
- Rhodesain is a major cysteine protease of <i>Trypanosoma brucei rhodesiense</i>, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. <b>2d</b>, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that <b>2d</b> is a slow-tight binder (<i>K</i><sub>i</sub> = 3 nM). Furthermore, the nonfluorinated <b>2d-(H)</b> shows favorable metabolism and biodistribution by accumulation in mice brain tissue after intraperitoneal and oral administration. The highest antitrypanosomal activity was observed for inhibitors with an N-terminal 2,3-dihydrobenzo[<i>b</i>][1,4]dioxine group and a 4-Me-Phe residue in P2 (<b>2e</b>/<b>4e</b>) with nanomolar EC<sub>50</sub> values (0.14/0.80 μM). The different mechanisms of reversible and irreversible inhibitors were explained using QM/MM calculations and MD simulations.
- Addresses
- Institute of Pharmaceutical and Biomedical Sciences (IPBS), Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
- Autoren
- Sascha Jung
- Natalie Fuchs
- Patrick Johe
- Annika Wagner
- Erika Diehl
- Tri Yuliani
- Collin Zimmer
- Fabian Barthels
- Robert A Zimmermann
- Philipp Klein
- Waldemar Waigel
- Jessica Meyr
- Till Opatz
- Stefan Tenzer
- Ute Distler
- Hans-Joachim Räder
- Christian Kersten
- Bernd Engels
- Ute A Hellmich
- Jochen Klein
- Tanja Schirmeister
- DOI
- 10.1021/acs.jmedchem.1c01002
- eISSN
- 1520-4804
- Externe Identifier
- PubMed Identifier: 34378914
- Funding acknowledgements
- Rhine-Main Universities Fund:
- Deutsche Forschungsgemeinschaft: EXC 2051 - Project ID390713860
- Open access
- false
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 16
- Zeitschrift
- Journal of medicinal chemistry
- Schlüsselwörter
- Hela Cells
- Animals
- Humans
- Mice
- Trypanosoma brucei brucei
- Sulfonic Acids
- Vinyl Compounds
- Sulfones
- Cysteine Endopeptidases
- Cysteine Proteinase Inhibitors
- Trypanocidal Agents
- Parasitic Sensitivity Tests
- Molecular Structure
- Protein Binding
- Structure-Activity Relationship
- Kinetics
- Female
- Male
- Enzyme Assays
- Molecular Docking Simulation
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2021
- Paginierung
- 12322 - 12358
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum der Datenerfassung
- 2021
- Titel
- Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies.
- Sub types
- Research Support, Non-U.S. Gov't
- Journal Article
- Ausgabe der Zeitschrift
- 64
Datenquelle: Europe PubMed Central
- Abstract
- Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorable metabolism and biodistribution by accumulation in mice brain tissue after intraperitoneal and oral administration. The highest antitrypanosomal activity was observed for inhibitors with an N-terminal 2,3-dihydrobenzo[b][1,4]dioxine group and a 4-Me-Phe residue in P2 (2e/4e) with nanomolar EC50 values (0.14/0.80 μM). The different mechanisms of reversible and irreversible inhibitors were explained using QM/MM calculations and MD simulations.
- Autoren
- Sascha Jung
- Natalie Fuchs
- Patrick Johe
- Annika Wagner
- Erika Diehl
- Tri Yuliani
- Collin Zimmer
- Fabian Barthels
- Robert A Zimmermann
- Philipp Klein
- Waldemar Waigel
- Jessica Meyr
- Till Opatz
- Stefan Tenzer
- Ute Distler
- Hans-Joachim Räder
- Christian Kersten
- Bernd Engels
- Ute A Hellmich
- Jochen Klein
- Tanja Schirmeister
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/34378914
- DOI
- 10.1021/acs.jmedchem.1c01002
- eISSN
- 1520-4804
- Ausgabe der Veröffentlichung
- 16
- Zeitschrift
- J Med Chem
- Schlüsselwörter
- Animals
- Cysteine Endopeptidases
- Cysteine Proteinase Inhibitors
- Enzyme Assays
- Female
- HeLa Cells
- Humans
- Kinetics
- Male
- Mice
- Molecular Docking Simulation
- Molecular Structure
- Parasitic Sensitivity Tests
- Protein Binding
- Structure-Activity Relationship
- Sulfones
- Sulfonic Acids
- Trypanocidal Agents
- Trypanosoma brucei brucei
- Vinyl Compounds
- Sprache
- eng
- Country
- United States
- Paginierung
- 12322 - 12358
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2021
- Titel
- Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 64
Datenquelle: PubMed
- Beziehungen:
- Eigentum von