The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin.
The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin.
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恶性疟原虫的热休克蛋白90和其抑制剂Geldanamycin的抗疟疾活性。
DOI：
10.1186/1475-2875-2-30
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发表时间：
2003-09-15
期刊：
影响因子：
3
通讯作者：
Barik S
中科院分区：
文献类型：
--
作者：
Kumar R;Musiyenko A;Barik S
天然存在的苯醌安沙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，是一种潜在的抗癌剂。由于据报道恶性疟原虫具有 Hsp90 直向同源物，我们测试了 GA 可能抑制它并从而表现出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 蛋白提供直接重组 DNA 证据。虽然 Hsp90 的 mRNA 主要在环期和滋养体阶段表达，但在所有阶段都发现了该蛋白质，尽管裂殖体中的含量相对较低。在体外，寄生的 Hsp90 表现出 ATP 结合活性，可以被 GA 特异性抑制。 GA 强烈抑制人红细胞培养物中的疟原虫生长，IC50 为 20 nM，而相同条件下氯喹 (CQ) 的 IC50 为 15 nM。当联合使用时，两种药物具有协同作用。 GA 对 CQ 敏感菌株和 CQ 抗性菌株（分别为 3D7 和 W2）以及所有红细胞阶段的寄生虫同样有效。总之，这些结果表明疟原虫中存在活跃且必需的 Hsp90 伴侣循环，并且安沙霉素抗生素将成为剖析其在寄生虫中的作用的重要工具。此外，人体试验中报告的 GA 良好的药理学使其成为一种有前途的抗疟药。
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.
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影响因子：
9.8
作者：
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通讯作者：
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作者：
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