Characterization of the protein interactors of Plasmodium falciparum Hsp70 (PfHsp70-1): towards the development of small-molecule inhibitors of PfHsp70-1 chaperone function

恶性疟原虫是引起热带疟疾的病原体，是造成疟疾造成的大多数死亡的原因。该疾病的病理学是寄生虫在人红细胞内生长和复制的结果。在宿主体内，寄生虫非常适应高温等应激条件;事实上，一些研究表明，急性温度升高会增强寄生虫的发育和感染性。该项目的主题是恶性疟原虫热休克蛋白70-1（PfHsp 70 -1），其在所有红细胞内阶段表达。Hsp 70蛋白是一个普遍存在的保守的分子伴侣家族，其主要功能是确保其他蛋白质底物的正确折叠，通常与其他热休克蛋白合作。虽然PfHsp 70 -1具有类似于哺乳动物Hsp 70的特性（伴侣功能，在应激条件下增加水平），但南非实验室的工作也揭示了生物化学上不同的特性。根据我们的工作假设，这些独特的特性代表了对细胞内和寄生生命的进化适应。因此，我们的目标是确定PfHsp 70 -1的功能伴侣蛋白和底物蛋白，以精确定义该蛋白的寄生虫特异性功能。最终目的是利用这些信息开发特异性抑制剂，作为新型抗疟疾药物的先导化合物。

Plasmodium falciparum is the causative agent of malaria tropica which is responsible for most of the deaths caused by malaria. The pathology of the disease is the result of parasite growth and replication within human erythrocytes. Within its host, the parasite is very well adapted to stress conditions such as high febrile temperatures; in fact several studies suggest that acute temperature increases augment parasite development and infectivity. The subject of this project is the P. falciparum heat shock protein 70-1 (PfHsp70-1) which is expressed throughout all intra-erythrocytic stages. Hsp70 proteins form a ubiquitous and conserved family of molecular chaperones whose main function is to ensure the correct folding of other protein substrates, usually in cooperation with other heat shock proteins. Although PfHsp70-1 has properties that are similar to mammalian Hsp70 (chaperone functions, increased levels under stress conditions), work in the South African laboratory have also revealed biochemically distinct properties. According to our working hypothesis, these distinct properties represent evolutionary adaptations to an intracellular and parasitic life. Therefore we aim to identify the functional partner proteins and substrate proteins of PfHsp70-1 to precisely define the parasite-specific functions of this protein. The ultimate aim is to use this information for the development of specific inhibitors as lead compounds for novel anti-malarial drugs.