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A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity

Sharlow, ER and Lyda, TA and Dodson, HC and Mustata, G and Morris, MT and Leimgruber, SS and Lee, KH and Kashiwada, Y and Close, D and Lazo, JS and Morris, JC (2010) A target-based high throughput screen yields Trypanosoma brucei hexokinase small molecule inhibitors with antiparasitic activity. PLoS Neglected Tropical Diseases, 4 (4).

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Background: The 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 c-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 Findings: Exploiting 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 ~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≤EC50<3 mM) 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. © 2010 Sharlow et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Sharlow, ER
Lyda, TA
Dodson, HC
Mustata, G
Morris, MT
Leimgruber, SS
Lee, KH
Kashiwada, Y
Close, Ddac71@pitt.eduDAC71
Lazo, JSlazo@pitt.eduLAZO
Morris, JC
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 April 2010
Date Type: Publication
Journal or Publication Title: PLoS Neglected Tropical Diseases
Volume: 4
Number: 4
DOI or Unique Handle: 10.1371/journal.pntd.0000659
Schools and Programs: School of Medicine > Computational Biology
Refereed: Yes
MeSH Headings: Antiparasitic Agents--chemistry; Antiparasitic Agents--isolation & purification; Antiparasitic Agents--pharmacology; Drug Evaluation, Preclinical--methods; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--isolation & purification; Enzyme Inhibitors--pharmacology; Hexokinase--antagonists & inhibitors; Humans; Protozoan Proteins--antagonists & inhibitors; Trypanosoma brucei brucei--drug effects; Trypanosoma brucei brucei--enzymology
Other ID: NLM PMC2854128
PubMed Central ID: PMC2854128
PubMed ID: 20405000
Date Deposited: 03 Aug 2012 18:59
Last Modified: 22 Jun 2021 14:56


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