Identification of Inhibitors of Trypanosoma Brucei Hexokinases

描述(申请人提供)：目前治疗非洲昏睡病的方法是有毒和无效的，这种疾病是由原虫寄生虫布鲁氏锥虫引起的。糖酵解是对抗布氏毛滴虫的一个很有希望的靶点，因为这条途径是必不可少的。己糖激酶(TbHK)的抑制剂是一种关键的糖酵解酶，已被证明对锥虫有毒性。由于锥虫的HKS与人类的HKS几乎没有相似性，它们是治疗开发的一个有前途的靶点。我们最近克隆和表达了具有活性的重组TbHK，并改进了标准的酶分析方法，用于高通量鉴定抑制剂。在这里，我们建议为分子文库筛选中心网络提供足够的重组蛋白(以及在高通量条件下监测其活性的方法)，以确定可能被证明是有用的先导化合物的抑制剂，作为抗锥虫药物和更好地了解TbHKs生物化学的工具。

DESCRIPTION (provided by applicant): Current therapies for African sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, are toxic and inefficacious. Glycolysis is a promising target in the fight against T. brucei, as the pathway is essential. Inhibitors of hexokinase (TbHK), a key glycolytic enzyme, have been shown to be toxic to trypanosomes. Since the trypanosomal HKs share little similarity with their human counterpart, they make a promising target for therapy development. We have recently cloned and expressed active recombinant TbHK, and have modified standard enzyme assays for high throughput identification of inhibitors. Here we propose to provide the Molecular Libraries Screening Centers Network with sufficient recombinant protein (and the methods used to monitor its activity under high throughput conditions) in order to identify inhibitors that may prove useful lead compounds as both anti-trypanosomal drugs and as tools for better understanding of the biochemistry of TbHKs.