ArticleThe Journal of biological chemistry2009
Chemical validation of trypanothione synthetase: a potential drug target for human trypanosomiasis.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 79 citations in OpenAlex.
- Targeting Trypanothione Synthetase and Trypanothione Reductase: Development of Common Inhibitors to Tackle Trypanosomatid Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Identification of Novel Antileishmanial Chemotypes By High-Throughput Virtual and In Vitro Screening.Acta parasitologica · 2024Article
- Targeting Trypanothione Metabolism in Trypanosomatids.Molecules (Basel, Switzerland) · 2024Review
- The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones.PloS one · 2023Article
- Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Is the mitochondrion a promising drug target in trypanosomatids?Memorias do Instituto Oswaldo Cruz · 2022Article
- Ensemble learning application to discover new trypanothione synthetase inhibitors.Molecular diversity · 2021Article
- Mechanistic and biological characterisation of novelJournal of enzyme inhibition and medicinal chemistry · 2020Article
- An overview of biochemically characterized drug targets in metabolic pathways of Leishmania parasite.Parasitology research · 2020Review
- Computational approaches for drug discovery against trypanosomatid-caused diseases.Parasitology · 2020Review
- Characterisation of a putative glutamate 5-kinase from Leishmania donovani.The FEBS journal · 2018Article
- Anti-trypanosomatid drug discovery: an ongoing challenge and a continuing need.Nature reviews. Microbiology · 2017Review
- Trypanosoma brucei DHFR-TS Revisited: Characterisation of a Bifunctional and Highly Unstable Recombinant Dihydrofolate Reductase-Thymidylate Synthase.PLoS neglected tropical diseases · 2016Article
- Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids.PLoS neglected tropical diseases · 2016Article
- Stage-dependent expression and up-regulation of trypanothione synthetase in amphotericin B resistant Leishmania donovani.PloS one · 2014Article
- The silicon trypanosome: a test case of iterative model extension in systems biology.Advances in microbial physiology · 2014Review
- Drug discovery for neglected diseases: molecular target-based and phenotypic approaches.Journal of medicinal chemistry · 2013Review
- Dissecting the catalytic mechanism of Trypanosoma brucei trypanothione synthetase by kinetic analysis and computational modeling.The Journal of biological chemistry · 2013Article
- Locating sweet spots for screening hits and evaluating pan-assay interference filters from the performance analysis of two lead-like libraries.Journal of chemical information and modeling · 2013Article
- Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase.PloS one · 2013Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
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 x EC(50) for 72 h) decreased intracellular trypanothione levels to <10% of wild type. In addition, there was a corresponding 5-fold increase in the precursor metabolite, glutathione, providing strong evidence that DDD86243 was acting on target to inhibit TryS. This was confirmed with wild-type, TryS single knock-out, and TryS-overexpressing cell lines showing expected changes in potency to DDD86243. Taken together, these data provide initial chemical validation of TryS as a drug target in T. brucei.
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