Protein Kinases of a Trypanosome

描述(申请人提供)：蛋白激酶是细胞增殖、迁移和分化的重要调节因子。许多类型的癌细胞过度表达蛋白激酶。抑制特定蛋白激酶的药物现在被用于治疗一些人类癌症。抗寄生虫药物的发现几乎没有得到制药业的支持，因为药物的客户很穷。“替代使用”药物发现，包括测试被批准用于控制非寄生虫疾病的药物，作为治疗寄生虫感染的治疗方法，是寻找新的先导化合物的具有成本效益的快速途径，可以作为抗寄生虫药物进行进一步研究。需要新的药物来治疗人类非洲锥虫病，这是由原虫寄生虫布氏锥虫引起的。我们的初步生物信息学和药理学研究表明，某些蛋白激酶对布氏毛滴虫的生存能力很重要，可能成为药物发现的靶点。在具体目标1中，我们将对抑制蛋白激酶的药物进行“重点筛选”，以找出其中哪些药物能在培养中杀死形成布氏毛滴虫的血流。有希望的抗锥虫先导化合物将在布氏锥虫感染的小鼠模型中进一步评估。在特定的目标2中，我们将结合亲和层析/化学蛋白质组学和分子遗传学的方法来验证蛋白激酶抑制剂的靶点。这些探索性/发育性(R21)研究的数据将为抗锥虫药物的发现提供新的先导化合物，并为未来描述蛋白激酶信号在布鲁氏锥虫中的生物学相关性的工作奠定基础。 与公共卫生相关：锥虫引起的疾病影响着全世界数百万人。这项建议中描述的工作可能会导致发现治疗人类非洲锥虫病的新药。

DESCRIPTION (provided by applicant): Protein kinases are important regulators of cell proliferation, migration, and differentiation. Cancer cells of many types over-express protein kinases. Drugs that inhibit specific protein kinases are now used to treat some human cancers. Anti-parasite drug discovery receives almost no support from the pharmaceutical industry, because the clients for the drugs are poor. "Alternative Use" drug discovery, which involves testing of drugs approved for control of non-parasitic diseases as treatment for parasite infections is a cost-effective and fast route for finding new lead compounds that may be studied further as anti-parasite drugs. Novel drugs are needed for treatment of human African trypanosomiasis, which is caused by the protozoan parasite Trypanosoma brucei. Our preliminary bioinformatic and pharmacological studies indicate that some protein kinases are important for viability and may be targeted for drug discovery in T. brucei. In Specific Aim 1, we will perform a "focused screen" of drugs that inhibit protein kinases to find out which of them kill blood stream form T. brucei in culture. Promising anti-trypanosome lead compounds will be evaluated further in a mouse model of T. brucei infection. In Specific Aim 2, we will validate the target of the protein kinase inhibitors, using a combination of affinity chromatography/chemical proteomics and molecular genetics approaches. Data from these exploratory/developmental (R21) studies will provide new lead compounds for anti-trypanosome drug discovery, and form the basis for a future work to delineate the biological relevance of protein kinase signaling in T. brucei. PUBLIC HEALTH RELEVANCE: Trypanosomes cause diseases that affect millions of people world-wide. Work described in this proposal may lead to discovery of new drugs for treatment of human African trypanosomiasis.