A Genetic System For Kinetoplastid Drug Discovery

描述(由申请人提供)：这个项目的目标是将一种新的、开发得很好的具有成本效益的药物靶标和药物发现方法应用于寄生虫病，重点是克氏锥虫和利什曼原虫，这两种疾病分别是恰加斯病和利什马尼亚病的病原体。该项目将产生比较的化合物筛选，以确定广泛适用于克氏锥虫和利什曼原虫的新的抗动态体化合物。广谱治疗药物的鉴定将大大增加新治疗药物的潜在市场，从而促进后来的商业化，这是一个重要的属性，因为大多数受影响的人口都很贫穷。这种实验方法利用了一种新的方法来识别与锥虫蛋白靶标特异相互作用但不与人类类似物相互作用的化合物。在该方法中，将克氏锥虫、利什曼原虫和人类基因导入酵母，在功能上取代了同源酵母基因。这些酵母菌株的集合，每个都携带不同的锥虫或人类基因(锥虫和人类Xenogene阵列)，可以用作高通量生物检测中的化合物筛选平台，以识别特定抑制人类Xenogene阵列中锥体靶标功能但不能抑制类似靶标功能的化合物。该应用还包括选定动质体靶向的试点小分子筛选。

DESCRIPTION (provided by applicant): The goal of this project is to apply a novel, well developed cost effective means of drug target and drug discovery to parasitic disease, focusing on Trypanosoma cruzi and Leishmania, the causative agents of Chagas disease and Leishmanaisis respectively. This project will generate comparative compound screens to identify new anti-kinetoplastid compounds that are broadly applicable to both T. cruzi and Leishmania species. The identification of broad-spectrum therapeutics will facilitate later commercialization by significantly increasing the potential market for new therapeutics, an important attribute since most of the afflicted populations are poor. The experimental approach exploits a novel method for identifying compounds that interact specifically with trypanosomal protein targets but not with the human analogs. In this method, T. cruzi, Leishmania sp., and human genes are introduced into yeast, functionally replacing the cognate yeast genes. A collection of these yeast strains, each bearing a different trypanosomatid or human gene (trypanosomatid and human XenoGene arrays), can be used as compound screening platforms in a high through-put bioassay to identify compounds which specifically inhibit the function of the trypanosome targets but not analogous targets in the human XenoGene array. This application also includes a pilot small molecule screen of selected kinetoplastid targets.