Chemical Validation of Trypanothione Synthetase
| Autor: | Paul G. Wyatt, Alan H. Fairlamb, Julie A. Frearson, Sandra L. Oza, Stephen Thompson, Daniel Spinks, Susan Wyllie, Justin R. Harrison, Leah S. Torrie, Ian H. Gilbert |
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| Rok vydání: | 2009 |
| Předmět: |
0303 health sciences
biology 030306 microbiology High-throughput screening Trypanothione Cell Biology Glutathione Trypanosoma brucei Pharmacology biology.organism_classification Biochemistry 3. Good health Spermidine 03 medical and health sciences chemistry.chemical_compound Enzyme activator chemistry Biosynthesis Drug development Molecular Biology 030304 developmental biology |
| Zdroj: | Journal of Biological Chemistry. 284:36137-36145 |
| ISSN: | 0021-9258 |
| Popis: | In the search for new therapeutics for the treatment of human African trypanosomiasis, many potential drug targets in Trypanosoma brucei have been validated by genetic means, but very few have been chemically validated. Trypanothione synthetase (TryS; EC 6.3.1.9; spermidine/glutathionylspermidine:glutathione ligase (ADP-forming)) is one such target. To identify novel inhibitors of T. brucei TryS, we developed an in vitro enzyme assay, which was amenable to high throughput screening. The subsequent screen of a diverse compound library resulted in the identification of three novel series of TryS inhibitors. Further chemical exploration resulted in leads with nanomolar potency, which displayed mixed, uncompetitive, and allosteric-type inhibition with respect to spermidine, ATP, and glutathione, respectively. Representatives of all three series inhibited growth of bloodstream T. brucei in vitro. Exposure to one of our lead compounds (DDD86243; 2 × EC50 for 72 h) decreased intracellular trypanothione levels to |
| Databáze: | OpenAIRE |
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