Iron chelators: Mode of action as antimalarials
Iron chelators: Mode of action as antimalarials
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DOI：
10.1159/000203952
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发表时间：
1996-01-01
影响因子：
2.4
通讯作者：
Tsafack, A
中科院分区：
文献类型：
--
作者：
Cabantchik, ZI;Glickstein, H;Tsafack, A
生长在人类红细胞内的疟疾寄生虫与哺乳动物细胞的不同之处在于，它们获取生物可利用的铁的方式不同，而且它们对铁络合剂的抗增殖作用的敏感性不同。我们在这里评估了与这些现象相关的三个主要性质：(A)寄生虫从宿主体内动员铁并将其整合到寄生虫蛋白质中的阶段依赖性；(B)质膜对铁络合剂的差异渗透性；以及(C)在感染细胞的细胞内环境中原位产生有毒的螯合剂-金属络合物。我们使用了合成铁络合剂和天然铁络合剂的组合，它们具有相似的铁结合性能，但渗透能力明显不同。从抑制浓度、作用速度、阶段依赖性和作用的可逆性等方面评价了这些药物对恶性疟原虫体外生长的作用情况。这些图谱为螯合剂对寄生细胞作用的工作模型提供了基础。该模型使我们能够预测，当铁络合剂用于慢速和快速渗透物质的适当组合时，其抗疟疾性能会有重大改善。体外发现的不同铁络合剂组合的协同作用符合该模型，并对治疗方案的设计具有指导意义。
Malaria parasites growing inside human eryhtrocytes differ from mammalian cells in their mode of acquisition of bioavailable iron and in their susceptibility to the antiproliferative action of iron chelators. We have assessed here three major properties associated with these phenomena: (a) the stage-dependent nature of parasite iron mobilization from the host and its integration into parasite proteins; (b) the differential permeability of the plasma membrane to iron chelators, and (c) the in situ generation of toxic chelator-metal complexes in the intracellular milieu of infected cells. We have used a combination of synthetic and natural iron chelators with similar iron-binding properties but markedly different capacities to permeate membranes. The profiles of action of these agents on the in vitro growth of Plasmodium falciparum were assessed in terms of inhibitory concentrations, speed of action, stage dependence and reversibility of effects. These profiles provided the basis for a working model of chelator action on parasitized cells. The model allowed us to predict major improvements in the antimalarial performance of iron chelators when used in appropriate combinations of slow- and fast-permeating substances. The synergistic actions found in vitro for various combinations of iron chelators are in accordance with the model and have implications for the design of therapeutic schemes.