Abstract
BackgroundSchistosomiasis, 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.MethodsA 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).ResultsWe 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.ConclusionThese confirmed hits may serve as starting points for the development of novel therapeutics to combat schistosomiasis.
Highlights
Schistosomiasis, a parasitic disease known as bilharzia and snail fever, is caused by different species of flatworms, such as Schistosoma mansoni (S. mansoni)
An earlier assay of the coupled activities of Schistosoma mansoni thioredoxin glutathione reductase (SmTGR) and peroxiredoxin-2 [13] was adapted to study the activity of SmTGR alone, using the following principle: SmTGR converts NADPH and Oxidized glutathione (GSSG) to NADP+ and reduced glutathione (GSH), and Reduced glutathione (GSH) production can be detected with ThioGlo®, a maleimide derivative of the naphthopyranone fluorophore which fluoresces upon reacting with free thiol groups such as those present in GSH
A recent study reported that RNAi helped validate novel and putative drug targets for schistosomiasis [20], Thioredoxin glutathione reductase (TGR) remains an attractive one and has been subject to high-throughput screening (HTS) studies using different assay systems [13, 21]
Summary
Schistosomiasis, a parasitic disease known as bilharzia and snail fever, is caused by different species of flatworms, such as Schistosoma mansoni (S. mansoni). Schistosome parasites infect an estimated 200 million people, of which 20 million have significant morbidity, resulting in more than 200,000 deaths annually. Previous studies have found significant differences between the redox network of schistosomes and their human hosts, with worm defenses being significantly less robust [6,7,8,9]. A screen against the schistosome redox pathway of TGR and peroxiredoxin-2 identified oxadiazole-2-oxides as novel TGR inhibitors with significant in vivo activity against laboratory infections [10,11,12,13]. Several novel compounds have been discovered with activity against SmTGR, cultured larval, and adult worms. These compounds may serve as starting points for the development of new therapeutic agents to combat schistosomiasis
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