Identification of Inhibitors of Trypanosoma Brucei Hexokinases

布氏锥虫己糖激酶抑制剂的鉴定

• 批准号: 7459260
• 负责人: JAMES Culvin MORRIS
• 金额: $ 2.5万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-29 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459260
• 关键词: Africa South of the Sahara; African Trypanosomiasis; Biochemical; Biochemistry; Biological; Biological Assay; Blood Circulation; Cell Survival; Cessation of life; Chromosomes, Human, Pair 10; Condition; Data; Development; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Future; Genes; Glucose; Glucose-6-Phosphate; Glycolysis; Human; Kinetics; Knock-out; Lead; Methods; Molecular Bank; Monitor; Parasites; Pathway interactions; Pharmaceutical Preparations; Proteins; RNA Interference; Recombinant Proteins; Recombinants; Research; Screening procedure; Standards of Weights and Measures; Trypanosoma; Trypanosoma brucei brucei; Universities; Work; design; fight against; follow-up; glucose metabolism; hexokinase; high throughput screening; in vivo; inhibitor/antagonist; man; polypeptide; programs; small molecule; therapeutic target; therapy development; tool

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.

描述（由申请人提供）：由原生动物寄生虫锥虫引起的非洲睡眠疗法的当前疗法是有毒的和无效的。糖酵解是对抗布鲁氏菌的斗争的一个有希望的目标，因为这条路是必不可少的。己糖激酶（TBHK）的抑制剂，一种关键的糖酵解酶，已证明对锥虫有毒。由于锥虫HKS与人类对应物的相似之处几乎没有相似之处，因此它们是治疗开发的有希望的目标。我们最近克隆并表达了活跃的重组TBHK，并修改了标准酶测定，以高通量鉴定抑制剂。在这里，我们建议为分子库筛选网络提供足够的重组蛋白（以及用于在高吞吐量条件下监测其活性的方法），以鉴定可能证明有用的铅化合物，作为抗肌体剂药物，又是抗肌体积药物的工具更好地了解TBHK的生物化学。