Chemically Mapping Malarial Rupture Proteases

描述（由申请人提供）：疟疾是一种毁灭性疾病，在许多发展中国家造成大量死亡。这种疾病最致命的形式是由机会性病原体恶性疟原虫引起的。人们已经做出了巨大的努力来了解寄生虫入侵宿主细胞并建立感染的过程，但对寄生虫在复制发生后介导其释放的过程知之甚少。这一过程对病原体的繁殖至关重要，阻断破裂的药物可能对开发新的抗疟疾药物有价值。这一建议概述计划使用小分子来研究蛋白酶的功能作用，调节宿主细胞破裂的过程。具体来说，它描述了使用蛋白酶抑制剂文库的表型筛选来识别阻止寄生虫从宿主红细胞释放的化合物。筛选命中将用于识别蛋白酶靶点，并剖析其调控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：该项目概述了使用小分子来鉴定寄生虫病原体恶性疟原虫所使用的蛋白酶的计划，该蛋白酶在人类宿主血液期感染期间介导宿主红细胞的破裂。这项工作将导致确定潜在的有价值的目标，以开发新的疟疾治疗策略。

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.