HTS Inhibitors:Schistosoma Mansoni Peroxiredoxins(RMI)

描述(申请人提供)：血吸虫病是一种重要的、使人衰弱的疾病，影响着70多个国家的约2.5亿人。据估计，在撒哈拉以南非洲，每年约有28万人死于这种疾病，而有2000万人患有极端残疾。在接下来的几年里，比尔和梅琳达·盖茨基金会和地方病国家项目将用一种广泛使用的抗血吸虫病药物--吡喹酮治疗数千万人。已经有临床和实验室证据表明存在对吡喹酮耐药的寄生虫，广泛使用预计会产生强大的耐药性选择压力。显然，迫切需要新的抗血吸虫药物。对血吸虫氧化还原平衡机制的研究表明，与人类宿主相比，血吸虫体内有一条截然不同的压缩途径。曼氏血吸虫Peroxiredoxins(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。我们的数据有力地表明了PRX作为新的药物靶点的可能性。首先，这些蛋白质是寄生虫生存所必需的。其次，这些蛋白表现出与宿主Prx蛋白足够的生化和结构差异。第三，这种蛋白质(S)可以在分子水平上进行研究，并可以在细菌中以可溶性和活性的形式大量产生。此外，PRX活性可以用高通量、廉价和灵敏的分析方法进行筛选。由于目前还没有寄生虫特异性的Prx抑制剂可用，我们的总体目标是通过对分子文库筛选中心网络(MLSCN)的小分子资料库进行高通量筛选来鉴定曼氏血吸虫Prx的抑制剂。这将是开发新的抗血吸虫化疗药物的第一步，这对继续采取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.