Protein Kinases of a Trypanosome

锥虫的蛋白激酶

• 批准号: 7897821
• 负责人: KOJO A. MENSA-WILMOT
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897821
• 关键词: AEE 788; Affect; Affinity Chromatography; African Trypanosomiasis; Antineoplastic Agents; Bioinformatics; Biological; Blood; Blood Circulation; Canertinib; Cell Proliferation; Chemicals; Client; Data; Development; Disease; Drug Delivery Systems; Drug Industry; Epidermal Growth Factor Receptor; Erlotinib; Foundations; Future; Gene Expression; Human; Infection; Lead; Malignant Neoplasms; Modeling; Molecular Genetics; Mus; Parasites; Parasitic Diseases; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Preclinical Drug Evaluation; Predisposition; Protein Kinase; Protein Kinase Inhibitors; Proteins; Proteomics; Role; Route; Signal Transduction; Stream; Testing; Trypanosoma; Trypanosoma brucei brucei; Work; base; cancer cell; cost; cost effective; drug discovery; drug testing; genome sequencing; inhibitor/antagonist; killings; migration; mouse model; novel; protein kinase inhibitor; public health relevance; theories

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.

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用于治疗某些人类癌症。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。“替代用途”药物发现涉及对批准用于控制非寄生虫病的药物进行测试，作为寄生虫感染的治疗，这是一种具有成本效益的快速途径，可用于发现可作为抗寄生虫药物进一步研究的新先导化合物。需要新的药物来治疗人类非洲锥虫病，这是由原生动物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，一些蛋白激酶对T细胞的存活率很重要，可能成为药物发现的靶点。布鲁塞。在具体目标1中，我们将对抑制蛋白激酶的药物进行“集中筛选”，以找出哪些药物能杀死T细胞的血流。文化中的布氏杆菌有希望的抗锥虫先导化合物将在小鼠T.布氏杆菌感染在具体目标2中，我们将使用亲和色谱/化学蛋白质组学和分子遗传学方法的组合来验证蛋白激酶抑制剂的靶点。这些探索性/发展性（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，并为未来的工作奠定基础，以描绘T.布鲁塞。 公共卫生相关性：锥虫引起的疾病影响了全世界数百万人。本提案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。

项目成果

Lapatinib-binding protein kinases in the African trypanosome: identification of cellular targets for kinase-directed chemical scaffolds.

• DOI: 10.1371/journal.pone.0056150
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Katiyar S;Kufareva I;Behera R;Thomas SM;Ogata Y;Pollastri M;Abagyan R;Mensa-Wilmot K
• 通讯作者: Mensa-Wilmot K