Disulfide redox balance in Schistosoma mansoni

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DESCRIPTION (provided by the applicant): Schistosomiasis is an important tropical parasitic human and veterinary disease. Although an inexpensive and highly effective anti-schistosome drug is in use 20 million individuals still suffer severe disease symptoms, transmission rates have changed little 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 chemotherapeutic agents. Schistosomes in their definitive and intermediate hosts must be able to survive in the presence of immune and self generated reactive oxygen compounds and provide disulfide-reducing equivalents for a number of critical enzymatic pathways. Two parallel detoxification/disulfide reduction systems occur in most organisms, one based on glutathione and the other based on thioredoxin. Recent results indicate that adult Schistosoma mansoni are deficient in glutathione reductase and thioredoxin reductase key enzymes in these pathways. Instead these activities are found together in a single protein thioredoxin glutathione reductase. This application proposes to investigate the role of thioredoxin glutathione reductase in parasite antioxidant defense and redox balance. The native protein will be purified and biochemically characterized. Active recombinant protein will be produced in order to carry out more extensive analysis. The role of the protein in redox defenses in vitro and in vivo will be investigated using known enzyme inhibitors. The stage and tissue expression of the enzyme will be determined. Because disulfide redox balance in schistosomes is centered on a single, key enzyme and is fundamentally different from host mechanisms we propose that this pathway is a promising target for novel, rational drug design.