New aziridine-based inhibitors of cathepsin L-like cysteine proteases with selectivity for the Leishmania cysteine protease LmCPB2.8
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Philipp Fey
- Roula Chartomatsidou
- Werner Kiefer
- Jeremy C Mottram
- Christian Kersten
- Tanja Schirmeister
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000443663200042&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.ejmech.2018.07.012
- eISSN
- 1768-3254
- Externe Identifier
- Clarivate Analytics Document Solution ID: GS4YG
- PubMed Identifier: 30029081
- ISSN
- 0223-5234
- Zeitschrift
- EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
- Schlüsselwörter
- Cysteine protease
- Inhibitor
- Aziridine
- Rhodesain
- Cruzain
- Leishmania
- Paginierung
- 587 - 597
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Titel
- New aziridine-based inhibitors of cathepsin L-like cysteine proteases with selectivity for the <i>Leishmania</i> cysteine protease LmCPB2.8
- Sub types
- Article
- Ausgabe der Zeitschrift
- 156
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Autoren
- Philipp Fey
- Roula Chartomatsidou
- Werner Kiefer
- Jeremy C Mottram
- Christian Kersten
- Tanja Schirmeister
- DOI
- 10.1016/j.ejmech.2018.07.012
- ISSN
- 0223-5234
- Zeitschrift
- European Journal of Medicinal Chemistry
- Sprache
- en
- Paginierung
- 587 - 597
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.ejmech.2018.07.012
- Datum der Datenerfassung
- 2019
- Titel
- New aziridine-based inhibitors of cathepsin L-like cysteine proteases with selectivity for the Leishmania cysteine protease LmCPB2.8
- Ausgabe der Zeitschrift
- 156
Datenquelle: Crossref
- Abstract
- In the present work a series of aziridine-2,3-dicarboxylate inhibitors of papain-like cysteine proteases was designed, synthesized and tested. The compounds displayed selectivity for the parasitic protozoon Leishmania mexicana cathepsin L-like cysteine protease LmCPB2.8. The computational methods of homology modelling and molecular docking predicted some significant differences in the S2 pocket of LmCPB2.8 and cruzain, a related enzyme from Trypanosoma cruzi. Due to the presence of Tyr209 in LmCPB2.8 rather than Glu208 in cruzain sterically demanding, lipophilic ester groups (inhibitor 7d, 9d, 12d and 14d) are predicted to occupy the S2 pocket of the Leishmania protease, but do not form favorable interactions in cruzain, which is in common with our experimental results. Further, inhibitor 18 bearing a free carboxylic acid attached to the aziridine moiety showed a time-dependent inhibition of LmCPB2.8 (K<sub>i</sub> = 0.41 μM; k<sub>2nd</sub> = 190,569 M<sup>-1</sup> min<sup>-1</sup>). Docking results suggested a strong ionic interaction with the positively charged His163 of the active site. Biological and theoretical data confirm that the novel selective aziridine-based inhibitors are promising candidates for further optimization as LmCPB2.8 inhibitors.
- Addresses
- Institut für Pharmazie und Biochemie, Johannes Gutenberg-Universität Mainz, Staudingerweg 5, 55128, Mainz, Germany.
- Autoren
- Philipp Fey
- Roula Chartomatsidou
- Werner Kiefer
- Jeremy C Mottram
- Christian Kersten
- Tanja Schirmeister
- DOI
- 10.1016/j.ejmech.2018.07.012
- eISSN
- 1768-3254
- Externe Identifier
- PubMed Identifier: 30029081
- Funding acknowledgements
- Medical Research Council: MR/K019384
- DFG: SFB630 PTA4
- Medical Research Council: MR/K019384/2
- Open access
- false
- ISSN
- 0223-5234
- Zeitschrift
- European journal of medicinal chemistry
- Schlüsselwörter
- Humans
- Leishmania
- Leishmania mexicana
- Leishmaniasis
- Leishmaniasis, Cutaneous
- Aziridines
- Cysteine Proteinase Inhibitors
- Antiparasitic Agents
- Drug Discovery
- Cathepsin L
- Molecular Docking Simulation
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2018
- Paginierung
- 587 - 597
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Datum der Datenerfassung
- 2018
- Titel
- New aziridine-based inhibitors of cathepsin L-like cysteine proteases with selectivity for the Leishmania cysteine protease LmCPB2.8.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 156
Datenquelle: Europe PubMed Central
- Abstract
- In the present work a series of aziridine-2,3-dicarboxylate inhibitors of papain-like cysteine proteases was designed, synthesized and tested. The compounds displayed selectivity for the parasitic protozoon Leishmania mexicana cathepsin L-like cysteine protease LmCPB2.8. The computational methods of homology modelling and molecular docking predicted some significant differences in the S2 pocket of LmCPB2.8 and cruzain, a related enzyme from Trypanosoma cruzi. Due to the presence of Tyr209 in LmCPB2.8 rather than Glu208 in cruzain sterically demanding, lipophilic ester groups (inhibitor 7d, 9d, 12d and 14d) are predicted to occupy the S2 pocket of the Leishmania protease, but do not form favorable interactions in cruzain, which is in common with our experimental results. Further, inhibitor 18 bearing a free carboxylic acid attached to the aziridine moiety showed a time-dependent inhibition of LmCPB2.8 (Ki = 0.41 μM; k2nd = 190,569 M-1 min-1). Docking results suggested a strong ionic interaction with the positively charged His163 of the active site. Biological and theoretical data confirm that the novel selective aziridine-based inhibitors are promising candidates for further optimization as LmCPB2.8 inhibitors.
- Date of acceptance
- 2018
- Autoren
- Philipp Fey
- Roula Chartomatsidou
- Werner Kiefer
- Jeremy C Mottram
- Christian Kersten
- Tanja Schirmeister
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/30029081
- DOI
- 10.1016/j.ejmech.2018.07.012
- eISSN
- 1768-3254
- Funding acknowledgements
- Medical Research Council: MR/K019384/2
- Zeitschrift
- Eur J Med Chem
- Schlüsselwörter
- Aziridine
- Cruzain
- Cysteine protease
- Inhibitor
- Leishmania
- Rhodesain
- Antiparasitic Agents
- Aziridines
- Cathepsin L
- Cysteine Proteinase Inhibitors
- Drug Discovery
- Humans
- Leishmania
- Leishmania mexicana
- Leishmaniasis
- Leishmaniasis, Cutaneous
- Molecular Docking Simulation
- Sprache
- eng
- Country
- France
- Paginierung
- 587 - 597
- PII
- S0223-5234(18)30568-3
- Datum der Veröffentlichung
- 2018
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2018
- Titel
- New aziridine-based inhibitors of cathepsin L-like cysteine proteases with selectivity for the Leishmania cysteine protease LmCPB2.8.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 156
Datenquelle: PubMed
- Beziehungen:
- Eigentum von