Malaria Phosphatase Inhibitors Identified as a Potential New Malaria Treatment

疟疾磷酸酶抑制剂被确定为潜在的新疟疾治疗方法

• 批准号: 8476279
• 负责人: KASTURI HALDAR
• 金额: $ 3.69万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-30 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8476279
• 关键词: Animals; Apical; Bacteria; Biological Assay; Blood; Cells; Child; Communicable Diseases; Complex; Culicidae; Drug Targeting; Drug resistance; Erythrocytes; Falciparum Malaria; Fever; Growth; Human; Infection; Invaded; Lead; Malaria; Membrane; Modeling; Molecular; Molecular Genetics; Organelles; Parasites; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphotyrosine; Plasmodium; Plasmodium falciparum; Prophylactic treatment; Proteins; Recombinant Proteins; Resistance; Signal Transduction; Specificity; Staging; Vacuole; Virulent; Vivax Malaria; base; drug development; high throughput screening; in vivo; inhibitor/antagonist; novel; parasite invasion; pathogen; phosphatase inhibitor; protein function; tool; transmission process; vaccine development

DESCRIPTION (provided by applicant): Malaria is a major infectious disease. Conservative estimates predict 2-300 million people are afflicted and over a million children die from the infection each year. The growing threat of drug resistant forms of malaria has created an urgent requirement for new drugs. Targeting unique features of host and parasite interactions provides one approach to new drug and vaccine development. Plasmodium falciparum causes the most virulent form of human malaria. To do this the parasite must secrete proteins that stimulate invasion of the erythrocyte which is critical to maintain blood stage infection. We have identified a novel phosphatase of the human malaria parasite P. falciparum that functions in parasite invasion of the erythrocyte and establishment of new vacuole. It is predicted to be active in mosquito stages, suggesting it may provide a target in transmission blocking as well. Further it is bacterial-like phosphatase present in all malarial species, suggesting that signaling via the phosphatase may be a conserved mechanism of infection that could be targeted to develop inhibitors as a new treatment for malaria. This is a new target and there are no compounds currently available for it and thus our studies will contribute to drugs that will be active agains parasites, which are otherwise resistant to other drugs and targets. Importantly, drugs against this phosphatase will be early 'acting' and thus rapidly reduce fever. Molecular, genetic tools using expression of recombinant protein and cell and animal analyses of this P.falciparum phosphatase will be used in conjunction with high throughput screening assays. These studies will be important for developing chemo prophylaxis directed against a brand new target in a major human pathogen.

描述（申请人提供）：疟疾是一种主要传染病。据保守估计，每年有2- 3亿人受到感染，100多万儿童死于感染。抗药性疟疾的威胁日益严重，迫切需要新的药物。靶向宿主和寄生虫相互作用的独特特征为新药和疫苗开发提供了一种方法。恶性疟原虫是最致命的人类疟疾。要做到这一点，寄生虫必须分泌刺激红细胞入侵的蛋白质，这对维持血液阶段感染至关重要。我们已经确定 人疟原虫恶性疟原虫的一种新型磷酸酶，在寄生虫侵入红细胞和建立新空泡中起作用。据预测，它在蚊子阶段是活跃的，这表明它也可能提供传播阻断的目标。此外，它是存在于所有疟疾物种中的细菌样磷酸酶，这表明通过磷酸酶的信号传导可能是一种保守的感染机制，可以靶向开发抑制剂作为疟疾的新疗法。这是一个新的靶点，目前还没有化合物可用于它，因此我们的研究将有助于开发对寄生虫有活性的药物，这些寄生虫对其他药物和靶点具有耐药性。重要的是，针对这种磷酸酶的药物将在早期“起作用”，从而迅速退烧。使用重组蛋白表达的分子、遗传工具以及该恶性疟原虫磷酸酶的细胞和动物分析将与高通量筛选测定结合使用。这些研究对于开发针对一种主要人类病原体中的全新靶点的化学预防将是重要的。