HTS Inhibitors:Schistosoma Mansoni Peroxiredoxins(RMI)

描述（由申请人提供）：血吸虫病是一种重要的使人衰弱的疾病，影响70多个国家的约2.5亿人。在撒哈拉以南非洲，这种疾病的年死亡率估计约为280 000人，同时有2 000万人患有严重残疾。在未来几年，比尔和梅林达盖茨基金会和流行国家计划将治疗数千万人与单一的抗血吸虫病药物广泛使用，吡喹酮。已有临床和实验室证据表明存在吡喹酮耐药性寄生虫，广泛使用预计会产生强大的抗药性选择压力。显然，迫切需要新的抗抑郁药物。对寄生虫体氧化还原平衡机制的研究表明，与人类宿主相比，寄生虫中存在一种独特的压缩途径。曼氏血吸虫过氧化物酶（Prx）是重要的寄生虫抗氧化蛋白，在氧化还原平衡机制中起着至关重要的作用。我们的数据强烈表明，可能使用的Prx作为新的药物靶点。首先，蛋白质是寄生虫生存所必需的。第二，蛋白质表现出足够的生化和结构的差异，从主机Prx蛋白。第三，蛋白质适合于在分子水平上研究，并且可以在细菌中以可溶性和活性形式大量产生。此外，Prx活性可以在高通量、廉价和灵敏的测定中进行筛选。由于没有寄生虫特异性抑制剂的Prx是目前可用的，我们的总体目标是通过进行高通量筛选的小分子库的分子库筛选中心网络（MLSCN）的曼氏血吸虫Prx的抑制剂的鉴定。这将是开发新型抗肿瘤化疗药物的第一步，这对持续的公共卫生措施至关重要。

DESCRIPTION (provided by applicant): Schistosomiasis is an important, debilitating disease affecting ~250 million people in more than 70 countries. The annual mortality of this disease is estimated to be ~280,000 in sub-Saharan Africa, while 20 million individuals suffer from extreme disability. In the coming years the Bill and Melinda Gates Foundation and endemic country programs will treat tens of millions of people with the single anti-schistosomiasis drug in widespread use, praziquantel. There is already clinical and laboratory evidence for the existence of praziquantel resistance parasites and widespread use is expected to generate strong selective pressure for drug resistance. Clearly, there is an urgent need for new anti-schistosome drugs. Studies on schistosome redox balance mechanisms indicate a distinct and compressed pathway in the parasite compared to its human host. Schistosoma mansoni peroxiredoxins (Prx) are important parasite antioxidant proteins that play a crucial role in redox balance mechanisms. Our data strongly suggest the possible use of Prx as novel drug targets. First, the proteins are essential for the parasite survival. Second, the proteins exhibits sufficient biochemical and structural differences from host Prx proteins. Third, the protein(s) is amenable for study at the molecular level and can be produced in bacteria in large quantities, in soluble and active form. Moreover, Prx activity can be screened in high throughput, inexpensive, and sensitive assays. Since no parasite-specific inhibitors of Prx are currently available, our overall goal is the identification of inhibitors of Schistosoma mansoni Prx by conducting a high throughput screen of the Small Molecule Repository of the Molecular Libraries Screening Centers Network (MLSCN). This will be the first step in the development of novel antischistosome chemotherapies, which are essential for continued public health measures.