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首页> 外文期刊>Parasitology >The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35
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The antimalarial action of FK506 and rapamycin: evidence for a direct effect on FK506-binding protein PfFKBP35

机译：FK506和雷帕霉素的抗疟疾作用：直接影响FK506结合蛋白PFFKBP35的证据

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摘要

FK506 and rapamycin (Rap) are immunosuppressive drugs that act principally on T-lymphocytes. The receptors for both drugs are FK506-binding proteins (FKBPs), but the molecular mechanisms of immunosuppression differ. An FK506-FKBP complex inhibits the protein phosphatase calcineurin, blocking a key step in T-cell activation, while the Rap - FKBP complex binds to the protein kinase target of rapamycin (TOR), which is involved in a subsequent signalling pathway. Both drugs, and certain non-immunosuppressive compounds related to FK506, have potent antimalarial activity. There is however conflicting evidence on the involvement of Plasmodium calcineurin in the action of FK506, and the parasite lacks an apparent TOR homologue. We therefore set out to establish whether inhibition of the Plasmodium falciparum FKBP PfFKBP35 itself might be responsible for the antimalarial effects of FK506 and Rap. Similarities in the antiparasitic actions of FK506 and Rap would constitute indirect evidence for this hypothesis. FK506 and Rap acted indistinguishably on: (i) specificity for different intra-erythrocytic stages in culture, (ii) kinetics of killing or irreversible growth arrest of parasites and (iii) interactions with other antimalarial agents. Furthermore, PfFKBP35's inhibitory effect on calcineurin was independent of FK506 under a range of conditions, suggesting that calcineurin is unlikely to be involved in the antimalarial action of FK506.
机译：FK506和雷帕霉素（RAP）是免疫抑制药物，其主要用于T淋巴细胞。两种药物的受体是FK506结合蛋白（FKBPS），但免疫抑制的分子机制不同。 FK506-FKBP复合物抑制蛋白质磷酸酶钙素素，阻断T细胞活化的关键步骤，而RAP - FKBP复合物结合雷帕霉素（TOR）的蛋白激酶靶标，其参与随后的信号通路。药物和某些与FK506相关的非免疫抑制化合物具有有效的抗疟活性。然而，关于疟原虫钙素在FK506的作用中的参与情况下存在矛盾的证据，并且寄生虫缺乏表观同源物。因此，我们旨在建立抑制疟原虫FKBP PFFKBP35本身的抑制可能对FK506和RAP的抗疟疾作用负责。 FK506和RAP的反诉行动中的相似之处将构成这一假设的间接证据。 FK506和RAP暂无区分：（i）培养物中不同红细胞阶段的特异性，（ii）杀灭寄生虫和（iii）与其他抗疟剂相互作用的杀伤或不可逆转的生长阻滞的动力学。此外，PffkBP35对钙素素的抑制作用在一系列条件下独立于FK506，表明钙素不太可能参与FK506的抗疟疾作用。

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