Schistosomiasis is an important tropical parasitic human disease. Although an effective anti-schistosome drug is in use, it is estimated that 200 million people remain infected, 20 million individuals suffer severe disease symptoms, and 280,000 people die annually from schistosomiasis. Furthermore, transmission rates have changed a little with the use of the drug and there is evidence for the development of drug resistant parasites. Because there is currently no suitable alternative therapy available there is an urgent need for the development of novel antischistosomal agents. In this application we propose to focus on parasite biochemical redox mechanisms as novel targets for antischistosomal drug development. Schistosomes in their definitive and intermediate hosts must be able to survive in the presence of both immune and self generated reactive oxygen compounds and provide disulfide reducing equivalents for a number of critical enzymatic pathways. Two parallel systems to provide oxidative defense and reducing power occur in most organisms, one based on glutathione and the other based on thioredoxin. Our recent results indicate that Schistosoma mansoni has fundamentally different redox mechanisms from their mammalian host. Entirely absent from worms are two key redox enzymes, glutathione reductase and thioredoxin reductase. Instead, these activities are found together in a single protein thioredoxin-glutathione reductase (TGR). We have shown that TGR is an essential parasite protein and that inhibition of the TGR leads to parasite death. In the research proposal we will: (1) synthesize potential TGR inhibitors based on lead compounds we have already identified and determine their relative inhibitory activity against parasite and host enzymes and their toxicity to cultured worms and mammalian cells, (2) develop an hypothesis for the catalytic mechanism of TGR, which will further the development of TGR inhibitors and, (3) define conditions suitable for the crystallization of TGR and determine its 3D structure for drug refinement. Because disulfide redox balance in schistosomes is centered on a single key redox enzyme and is fundamentally different from host mechanisms we propose in exploit this parasite pathway as a promising target for rational drug design. ? ? ?
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