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）：由原生动物寄生虫布氏锥虫引起的非洲昏睡病的现有疗法是有毒且无效的。糖酵解是抗T.布氏杆菌，因为该途径至关重要。己糖激酶（TbHK）是一种关键的糖酵解酶，其抑制剂对锥虫具有毒性。由于锥虫HK与其人类对应物几乎没有相似性，因此它们成为治疗开发的有希望的靶标。我们最近克隆和表达活性重组TbHK，并修改了标准的酶测定抑制剂的高通量鉴定。在这里，我们建议提供足够的重组蛋白的分子库筛选中心网络（和用于监测其在高通量条件下的活性的方法），以确定抑制剂，可能证明有用的先导化合物作为抗锥虫药物和工具，更好地了解生化TbHK。