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Biological evaluation and x-ray co-crystal structures of cyclohexylpyrrolidine ligands for trypanothione reductase, an enzyme from the redox metabolism of trypanosoma

De Gasparo, Raoul and Brodbeck-Persch, Elke and Bryson, Steve and Hentzen, Nina B. and Kaiser, Marcel and Pai, Emil F. and Krauth-Siegel, R. Luise and Diederich, François. (2018) Biological evaluation and x-ray co-crystal structures of cyclohexylpyrrolidine ligands for trypanothione reductase, an enzyme from the redox metabolism of trypanosoma. ChemMedChem, 13 (9). pp. 957-967.

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Abstract

The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (K; i; ) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half-maximal inhibitory concentration, IC; 50; ) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X-ray co-crystal structures confirmed the binding of the ligands to the hydrophobic wall of the "mepacrine binding site" with the new, solubility-providing vectors oriented toward the surface of the large active site.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:1860-7179
e-ISSN:1860-7187
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
Identification Number:
Last Modified:07 Sep 2018 13:31
Deposited On:03 Jul 2018 10:48

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