Chemically Mapping Malarial Rupture Proteases

描述(申请人提供)：疟疾是一种破坏性疾病，在发展中世界的许多国家造成重大死亡。这种疾病最致命的形式是由条件致病菌恶性疟原虫引起的。人们已经做出了大量的努力来了解寄生虫入侵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，而阻断破裂的药物很可能作为新的抗疟疾药物而具有开发价值。这项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。具体地说，它描述了使用使用蛋白酶抑制剂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HITS将被用来识别蛋白酶靶标，并剖析它们对宿主细胞破裂的调控细节。最后，先导化合物将应用于疟疾的小鼠模型，以验证多种蛋白酶作为新的抗疟疾疗法的药物靶点。与公共卫生相关：该项目概述了使用小分子来识别恶性疟原虫病原体所使用的蛋白酶的计划，以在人类宿主的血液期感染期间调节宿主红细胞的破裂。这项工作将导致确定制定新的疟疾治疗战略的潜在有价值的目标。

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.