3-aminooxy-1-aminopropane and derivatives have an antiproliferative effect on cultured Plasmodium falciparum by decreasing intracellular polyamine concentrations
3-aminooxy-1-aminopropane and derivatives have an antiproliferative effect on cultured Plasmodium falciparum by decreasing intracellular polyamine concentrations
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DOI：
10.1128/aac.49.7.2857-2864.2005
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发表时间：
2005-07-01
影响因子：
4.9
通讯作者：
Lüersen, K
中科院分区：
文献类型：
--
作者：
Das Gupta, R;Krause-Ihle, T;Lüersen, K
恶性疟原虫在红细胞内的发育与感染红细胞中多胺腐胺、亚精胺和精胺水平的增加有关；隔室分析表明，大多数与恶性疟原虫有关。由于耗尽细胞型多胺是抑制寄生虫增殖的一种有前景的策略，因此对新型多胺生物合成抑制剂的抗疟疾活性进行了测试。鸟氨酸脱羧酶抑制剂3-氨氧基-1-氨基丙烷及其衍生物CGP52622A和CGP54169A以及S腺苷蛋氨酸脱羧酶抑制剂CGP40215A和CG48664A对双功能恶性疟原虫ODCAMetDC有较强的抑制作用，其K-I值分别在低纳摩尔和低微摩尔范围内。此外，在48小时的孵育试验中，检测了这些试剂的体外杀浆活性。APA、CGP52622A、CGP54169A和CGP40215A的抑制作用最强，半数抑制浓度在3mU以下，腐胺和亚精胺不能拮抗ADOMetDC抑制剂CGP40215A的抑制作用。此外，CGP 40215A不影响细胞内多胺水平，提示其抗恶性疟原虫的作用机制不依赖于多胺的合成。相反，ODC抑制剂导致恶性疟原虫细胞腐胺和亚精胺水平下降，支持它们通过抑制双功能ODC-ADOMetDC发挥抗疟疾活性的事实。
The intraerythrocytic development of Plasmodium falciparum correlates with increasing levels of the polyamines putrescine, spermidine, and spermine in the infected red blood cells; and compartmental analyses revealed that the majority is associated with the parasite. Since depletion of cellular polyamines is a promising strategy for inhibition of parasite proliferation, new inhibitors of polyamine biosynthesis were tested for their antimalarial activities. The ornithine decarboxylase (ODC) inhibitor 3-aminooxy-1-aminopropane (APA) and its derivatives CGP 52622A and CGP 54169A as well as the S-adenosylmethionine decarboxlyase (AdoMetDC) inhibitors CGP 40215A and CGP 48664A potently affected the bifunctional P. falciparum ODC-AdoMetDC, with K-i values in the low nanomolar and low micromolar ranges, respectively. Furthermore, the agents were examined for their in vitro plasmodicidal activities in 48-h incubation assays. APA, CGP 52622A, CGP 54169A, and CGP 40215A were the most effective, with 50% inhibitory concentrations below 3 mu M. While the effects of the ODC inhibitors were completely abolished by the addition of putrescine, growth inhibition by the AdoMetDC inhibitor CGP 40215A could not be antagonized by putrescine or spermidine. Moreover, CGP 40215A did not affect the cellular polyamine levels, indicating a mechanism of action against P. falciparum independent of polyamine synthesis. In contrast, the ODC inhibitors led to decreased cellular putrescine and spermidine levels in falciparum, supporting the fact that they exert their antimalarial activities by inhibition of the bifunctional ODC-AdoMetDC.