Malaria Phosphatase Inhibitors Identified as a Potential New Malaria Treatment

描述(申请人提供)：疟疾是一种主要的传染病。保守估计，每年有200-3亿人受到这种疾病的困扰，超过100万儿童死于这种感染。抗药性疟疾的威胁越来越大，这对新药产生了迫切的需求。针对宿主和寄生虫相互作用的独特特征，为新药和疫苗的开发提供了一种途径。恶性疟原虫是人类疟疾中最致命的一种。要做到这一点，寄生虫必须分泌刺激红细胞入侵的蛋白质，这对维持血液期感染至关重要。我们已经确定了 恶性疟原虫一种新的人类恶性疟原虫磷酸酶，作用于寄生虫入侵红细胞和建立新的液泡。据预测，它在蚊子阶段活跃，这表明它也可能成为阻断传播的靶标。此外，它是一种细菌样磷酸酶，存在于所有疟疾物种中，这表明通过磷酸酶传递信号可能是一种保守的感染机制，可以作为靶向开发抑制剂作为疟疾的新治疗方法。这是一个新的靶点，目前还没有可用于它的化合物，因此我们的研究将有助于开发对寄生虫具有活性的药物，否则这些药物和靶点对其他药物和靶点具有抗药性。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。利用重组蛋白表达、细胞和动物分析的分子、遗传工具将与高通量筛选试验结合使用。这些研究对于开发针对人类主要病原体的全新靶点的化学预防将是重要的。

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.