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Evaluation of Small Molecule Inhibitors of Hemoglobin Transport as Antimalarials

血红蛋白转运小分子抑制剂作为抗疟药的评价

基本信息

批准号：
8320098
负责人：
Theodore F Taraschi
金额：
$ 19.38万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2014-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): We've developed a new model for the internalization and transport of hemoglobin from host erythrocyte cytosol to the digestive vacuole (DV) in intraerythrocytic Plasmodium falciparum malaria parasites. The examination of serial sections by electron microscopy of malaria infected erythrocytes (IRBC) revealed that cytostomes extend to and fuse with the parasite digestive vacuole (DV), thereby delivering hemoglobin to the parasite. This process was dependent on actin dynamics, as agents that stabilize actin filaments prevented the delivery of hemoglobin to the DV. Furthermore, we demonstrated that the delivery of hemoglobin to the DV was an obligate process, as inhibition of this process inhibited parasite development and caused parasite death. More recently, using a specific small molecule GTPase inhibitor, we disrupted the cytostome morphology and prevented hemoglobin transport to the DV, resulting in the arrest of parasite development. Our new discoveries reveal that the inhibition of hemoglobin delivery to the DV is lethal to P. falciparum parasites and as a result validated this process as a new target for antimalarial therapy. We seek to capitalize on our observations to develop an in vitro assay to monitor hemoglobin transport to the DV (as a read out) and use it to screen a small molecule library for compounds that inhibit this process and parasite development. Validation experiments in vitro of positive hits from the small molecule screen will be performed prior to moving into in vivo testing down the road. Perturbing the hemoglobin transport system represents a unique approach for developing antimalarials. Given the urgent need for new drug targets and antimalarials and the millions of people worldwide afflicted by malaria, the potential impact of this project is very high.

描述（由申请人提供）：我们建立了红细胞恶性疟原虫疟原虫血红蛋白从宿主红细胞胞浆内化和运输到消化液泡（DV）的新模型。疟疾感染红细胞（IRBC）的电镜连续切片检查显示，胞口延伸到寄生虫的消化液泡（DV）并与之融合，从而向寄生虫输送血红蛋白。这一过程依赖于肌动蛋白动力学，因为稳定肌动蛋白丝的药物阻止了血红蛋白向DV的传递。此外，我们证明血红蛋白传递到DV是一个专性过程，因为抑制这一过程会抑制寄生虫的发育并导致寄生虫死亡。最近，我们使用一种特定的小分子GTPase抑制剂，破坏了胞壁形态，阻止了血红蛋白向DV的运输，从而阻止了寄生虫的发育。我们的新发现表明，抑制血红蛋白向DV的传递对恶性疟原虫是致命的，从而验证了这一过程作为抗疟疾治疗的新靶点。我们试图利用我们的观察结果来开发一种体外试验，以监测血红蛋白向DV的运输（作为读出），并使用它来筛选抑制这一过程和寄生虫发展的化合物的小分子文库。在进入体内测试之前，将进行小分子筛选的阳性反应的体外验证实验。干扰血红蛋白运输系统是开发抗疟药物的一种独特方法。鉴于迫切需要新的药物靶点和抗疟疾药物，以及全世界数百万人受到疟疾的折磨，该项目的潜在影响非常大。