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）：我们已经开发了一种新的模型，用于将血红蛋白从宿主红细胞胞质醇内在化和运输到消化液泡（DV）中，在炎性细胞内疟原虫疟原虫寄生虫中。通过电子显微镜检查疟疾感染红细胞（IRBC）的系列切片表明，细胞抑制剂延伸至寄生虫消化液（DV），从而向寄生虫传递血红蛋白。这个过程取决于肌动蛋白动力学，因为稳定肌动蛋白丝的药物阻止了血红蛋白传递到DV。此外，我们证明了血红蛋白向DV的递送是一个强制性过程，因为对这一过程的抑制会抑制寄生虫的发育并导致寄生虫死亡。最近，使用特定的小分子GTPase抑制剂，我们破坏了细胞抑制剂的形态，并防止了血红蛋白转运到DV，从而导致寄生虫发育停滞。我们的新发现表明，对DV的抑制作用对恶性疟原虫寄生虫是致命的，因此，这一过程证实了这一过程是抗疟疾治疗的新靶标。我们试图利用我们的观察结果来开发一种体外测定法，以监测到DV的血红蛋白传输（作为读出），并使用它来筛选一个小分子库，以抑制这种过程和寄生虫的发育。在进行体内测试之前，将进行小分子筛选的正命中验证实验。扰动血红蛋白传输系统代表着一种开发抗疟药的独特方法。鉴于迫切需要新的药物靶标和抗疟疾药物以及全世界遭受疟疾折磨的数百万人，因此该项目的潜在影响很高。