High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis
Autor: | Min He, Ting Li, Peter Ziniel, Valerie P. Kommer, David L. Williams, Wesley C. Van Voorhis, Gregory J. Crowther, Panqing He, Ming-Wei Wang, Qing Liu |
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Rok vydání: | 2015 |
Předmět: |
Inhibitor
High-throughput screening Drug Evaluation Preclinical Parasitic Sensitivity Tests Schistosomiasis Snail Pharmacology Thioredoxin glutathione reductase Small Molecule Libraries Schistosomicides Multienzyme Complexes biology.animal parasitic diseases medicine Animals Humans NADH NADPH Oxidoreductases Enzyme Inhibitors chemistry.chemical_classification biology Public Health Environmental and Occupational Health Reproducibility of Results Schistosoma mansoni General Medicine biology.organism_classification medicine.disease High-Throughput Screening Assays Infectious Diseases Enzyme chemistry Parasitic disease Immunology Research Article |
Zdroj: | Infectious Diseases of Poverty |
ISSN: | 2049-9957 |
Popis: | Background Schistosomiasis, a parasitic disease also known as bilharzia and snail fever, is caused by different species of flatworms, such as Schistosoma mansoni (S. mansoni). Thioredoxin glutathione reductase (TGR) from S. mansoni (SmTGR) is a well-characterized drug target for schistosomiasis, yet no anti-SmTGR compounds have reached clinical trials, suggesting that therapeutic development against schistosomiasis might benefit from additional scaffolds targeting this enzyme. Methods A high-throughput screening (HTS) assay in vitro against SmTGR was developed and applied to a diverse compound library. SmTGR activity was quantified with ThioGlo®, a reagent that fluoresces upon binding to the free sulfhydryl groups of the reaction product GSH (reduced glutathione). Results We implemented an HTS effort against 59,360 synthetic compounds. In the primary screening, initial hits (928 or 1.56 %) showing greater than 90 % inhibition on SmTGR activity at a final concentration of 10 μM for each compound were identified. Further tests were carried out to confirm the effects of these hits and to explore the concentration-dependent response characteristics. As a result, 74 of them (0.12 %) representing 17 chemical scaffolds were confirmed and showed a great concentration-dependent inhibitory trend against SmTGR, including structures previously shown to be lethal to schistosomal growth. Of these, two scaffolds displayed a limited structure-activity relationship. When tested in cultured larvae, 39 compounds had cidal activity in 48 h, and five of them killed larvae completely at 3.125 μM. Of these, three compounds also killed adult worms ex vivo at concentrations between 5 μM and 10 μM. Conclusion These confirmed hits may serve as starting points for the development of novel therapeutics to combat schistosomiasis. |
Databáze: | OpenAIRE |
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