ArticlePLoS neglected tropical diseases2010
A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity.
Article in PLoS neglected tropical diseases, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 59 citations in OpenAlex.
- Transcriptomic and metabolomic insights into the long-term survival strategies of Ophiocordyceps sinensis following host immune perturbation.BMC microbiology · 2026Article
- Glucose metabolism in the pathogenic free-living amoebae: Tempting targets for treatment development.Chemical biology & drug design · 2024Review
- Enolase Inhibitors as Early Lead Therapeutics againstPathogens (Basel, Switzerland) · 2023Article
- Molecular characterisation of Entamoeba histolytica UDP-glucose 4-epimerase, an enzyme able to provide building blocks for cyst wall formation.PLoS neglected tropical diseases · 2023Article
- Isolation of Glycosomes from Trypanosoma brucei.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Drug-like molecules with anti-trypanothione synthetase activity identified by high throughput screening.Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Tryp-ing Up Metabolism: Role of Metabolic Adaptations in Kinetoplastid Disease Pathogenesis.Infection and immunity · 2021Review
- Proposed Mechanism for the Antitrypanosomal Activity of Quercetin and Myricetin Isolated fromMolecules (Basel, Switzerland) · 2021Article
- Computational approaches for drug discovery against trypanosomatid-caused diseases.Parasitology · 2020Review
- Enzymatic and Structural Characterization of theAntimicrobial agents and chemotherapy · 2019Article
- Optimization and Evaluation of Antiparasitic Benzamidobenzoic Acids as Inhibitors of Kinetoplastid Hexokinase 1.ChemMedChem · 2017Article
- A targeted delivery strategy for the development of potent trypanocides.Chemical communications (Cambridge, England) · 2017Article
- Antiparasitic lethality of sulfonamidebenzamides in kinetoplastids.Bioorganic & medicinal chemistry letters · 2017Article
- Evaluation of substituted ebselen derivatives as potential trypanocidal agents.Bioorganic & medicinal chemistry letters · 2017Article
- Identification of Novel Plasmodium falciparum Hexokinase Inhibitors with Antiparasitic Activity.Antimicrobial agents and chemotherapy · 2016Article
- Structure-based approach to the identification of a novel group of selective glucosamine analogue inhibitors of Trypanosoma cruzi glucokinase.Molecular and biochemical parasitology · 2015Article
- Three-dimensional structures in the design of therapeutics targeting parasitic protozoa: reflections on the past, present and future.Acta crystallographica. Section F, Structural biology communications · 2015Review
- Advanced enzymology, expression profile and immune response of Clonorchis sinensis hexokinase show its application potential for prevention and control of clonorchiasis.PLoS neglected tropical diseases · 2015Article
- Precursor-Directed Combinatorial Biosynthesis of Cinnamoyl, Dihydrocinnamoyl, and Benzoyl Anthranilates in Saccharomyces cerevisiae.PloS one · 2015Article
- In silico search of energy metabolism inhibitors for alternative leishmaniasis treatments.BioMed research international · 2015Article
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Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
Abstract
backgroundThe parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the gamma-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay. METHODOLOGY/PRINCIPAL
findingsExploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were approximately 20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03<or=EC(50)<3 microM) with parasite specificity of the compounds being demonstrated using insect stage T. brucei parasites, Leishmania promastigotes, and mammalian cell lines. Analysis of two structurally related compounds, ebselen and SID 17387000, revealed that both were mixed inhibitors of TbHK1 with respect to ATP. Additionally, both compounds inhibited parasite lysate-derived HK activity. None of the compounds displayed structural similarity to known hexokinase inhibitors or human African trypanosomiasis therapeutics. CONCLUSIONS/SIGNIFICANCE: The novel chemotypes identified here could represent leads for future therapeutic development against the African trypanosome.
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