Disulfide redox balance in Schistosoma mansoni

描述（由申请人提供）：血吸虫病是一种重要的热带人畜寄生虫病。虽然正在使用一种廉价和高效的抗血吸虫药物，但仍有2 000万人出现严重的疾病症状，但传播率变化不大，而且有证据表明出现了耐药寄生虫。由于目前还没有合适的替代疗法，因此迫切需要开发新的化疗药物。血吸虫在其最终宿主和中间宿主中必须能够在免疫和自身产生的活性氧化合物存在下存活，并为许多关键的酶促途径提供二硫还原等量物。在大多数生物体中发生两种平行的解毒/二硫还原系统，一种基于谷胱甘肽，另一种基于硫氧还蛋白。最近的研究结果表明，成年曼氏血吸虫在这些途径中缺乏谷胱甘肽还原酶和硫氧还蛋白还原酶。相反，这些活动是在单一蛋白质硫氧还蛋白谷胱甘肽还原酶中发现的。本研究旨在探讨硫氧还蛋白谷胱甘肽还原酶在寄生虫抗氧化防御和氧化还原平衡中的作用。天然蛋白将被纯化并进行生化表征。将生产活性重组蛋白，以便进行更广泛的分析。该蛋白在体外和体内氧化还原防御中的作用将使用已知的酶抑制剂进行研究。将确定酶的阶段和组织表达。由于血吸虫的二硫氧化还原平衡集中在一个单一的关键酶上，并且与宿主机制根本不同，我们认为这一途径是新型合理药物设计的一个有希望的靶点。

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.