Kumar Rajinder, Musiyenko Alla, Barik Sailen
Department of Biochemistry and Molecular Biology (MSB 2370), University of South Alabama, College of Medicine, 307 University Blvd, Mobile, AL 36688-0002, USA.
Malar J. 2003 Sep 15;2:30. doi: 10.1186/1475-2875-2-30.
The naturally occurring benzoquinone ansamycin compound, geldanamycin (GA), is a specific inhibitor of heat shock protein 90 (Hsp90) and is a potential anticancer agent. Since Plasmodium falciparum has been reported to have an Hsp90 ortholog, we tested the possibility that GA might inhibit it and thereby display antiparasitic activity.
We provide direct recombinant DNA evidence for the Hsp90 protein of Plasmodium falciparum, the causative agent of fatal malaria. While the mRNA of Hsp90 was mainly expressed in ring and trophozoite stages, the protein was found in all stages, although schizonts contained relatively lower amounts. In vitro the parasitic Hsp90 exhibited an ATP-binding activity that could be specifically inhibited by GA. Plasmodium growth in human erythrocyte culture was strongly inhibited by GA with an IC50 of 20 nM, compared to the IC50 of 15 nM for chloroquine (CQ) under identical conditions. When used in combination, the two drugs acted synergistically. GA was equally effective against CQ-sensitive and CQ-resistant strains (3D7 and W2, respectively) and on all erythrocytic stages of the parasite.
Together, these results suggest that an active and essential Hsp90 chaperone cycle exists in Plasmodium and that the ansamycin antibiotics will be an important tool to dissect its role in the parasite. Additionally, the favorable pharmacology of GA, reported in human trials, makes it a promising antimalarial drug.
天然存在的苯醌安莎霉素化合物格尔德霉素（GA）是热休克蛋白90（Hsp90）的特异性抑制剂，是一种潜在的抗癌药物。由于据报道恶性疟原虫有一个Hsp90直系同源物，我们测试了GA可能抑制它并从而显示抗寄生虫活性的可能性。
我们为致命疟疾的病原体恶性疟原虫的Hsp90蛋白提供了直接的重组DNA证据。虽然Hsp90的mRNA主要在环状体和滋养体阶段表达，但在所有阶段都发现了该蛋白，尽管裂殖体中的含量相对较低。在体外，寄生的Hsp90表现出一种ATP结合活性，可被GA特异性抑制。在人红细胞培养中，GA强烈抑制疟原虫生长，IC50为20 nM，而在相同条件下氯喹（CQ）的IC50为15 nM。联合使用时，这两种药物具有协同作用。GA对CQ敏感和CQ耐药菌株（分别为3D7和W2）以及疟原虫的所有红细胞内阶段同样有效。
总之，这些结果表明疟原虫中存在一个活跃且必需的Hsp90伴侣循环，并且安莎霉素类抗生素将是剖析其在寄生虫中作用的重要工具。此外，在人体试验中报道的GA良好药理学特性使其成为一种有前景的抗疟药物。
