Chemically Mapping Malarial Rupture Proteases

描述（由申请人提供）：疟疾是一种毁灭性的疾病，在许多发展中国家造成严重死亡。这种疾病最致命的形式是由机会致病菌恶性疟原虫引起的。已经做出了重大努力来了解寄生虫侵入宿主细胞以建立感染的过程，但对寄生虫在复制发生后介导其释放的过程知之甚少。这一过程对于病原体的繁殖是必不可少的，并且阻断破裂的试剂可能对于开发新的抗疟疾剂是有价值的。该提案概述了使用小分子来研究调节宿主细胞破裂过程的蛋白酶的功能作用的计划。具体而言，它描述了使用蛋白酶抑制剂文库进行表型筛选以鉴定阻断寄生虫从宿主红细胞释放的化合物的用途。筛选命中将被用来确定蛋白酶的目标，并剖析其调节宿主细胞破裂的细节。最后，先导化合物将应用于疟疾小鼠模型，以验证多种蛋白酶作为新型抗疟疾疗法的药物靶点。公共卫生相关性：该项目概述了计划使用小分子来识别寄生虫病原体恶性疟原虫使用的蛋白酶，以介导人类宿主血液阶段感染期间宿主红细胞的破裂。这项工作将导致确定潜在的有价值的目标，以制定新的疟疾治疗战略。

DESCRIPTION (provided by applicant): Malaria is a devastating disease that causes significant mortality in many countries of the developing world. The most deadly form of the disease is caused by the opportunistic pathogen, Plasmodium falciparum. Significant efforts have been made to understand the process by which the parasite invades a host cell to establish infection, yet relatively little is known about the process by which the parasite mediates its release after replication has occurred. This process is essential for propagation of the pathogen and agents that block rupture are likely to be valuable for development as novel anti-malarial agents. This proposal outlines plans to use small molecules to study the functional roles of proteases that regulate the process of host cell rupture. Specifically, it describes the use of phenotypic screens using libraries of protease inhibitors to identify compounds that block the release of parasites from host red blood cells. Screening hits will be used to identify protease targets and to dissect the details of their regulation of host cell rupture. Finally, lead compounds will be applied to mouse models of malaria to validate multiple proteases as drug targets for novel anti-malarial therapies. PUBLIC HEALTH RELEVANCE: This project outlines plans to use small molecules to identify proteases used by the parasite pathogen, Plasmodium falciparum, to mediate rupture of host red blood cells during the blood stage infection of a human host. This work will lead to the identification of potentially valuable targets for development of new therapeutic treatment strategies for malaria.