Accumulation of artemisinin trioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent.
Accumulation of artemisinin trioxane derivatives within neutral lipids of Plasmodium falciparum malaria parasites is endoperoxide-dependent.
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DOI：
10.1016/j.bcp.2008.10.015
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发表时间：
2009-02-01
影响因子：
5.8
通讯作者：
Cooper, Roland A.
中科院分区：
文献类型：
--
作者：
Hartwig, Carmony L.;Rosenthal, Andrew S.;D'Angelo, John;Griffin, Carol E.;Posner, Gary H.;Cooper, Roland A.
以天然存在的倍半萜内酯青蒿素及其半合成衍生物为例的抗疟三环类药物，含有内过氧化物药效团，具有对抗疟原虫的巨大效力。尽管经过数十年的研究，它们的作用机制仍未得到解决。抗疟原虫活性的主要模型假设铁介导的内过氧化物桥的裂解产生能够破坏细胞大分子的细胞毒性药物代谢物。为了探索内过氧化物药物的疟疾靶点，我们利用显微镜成像技术研究了荧光丹酰三氧环衍生物在活的红细胞内恶性疟原虫中的分布。荧光三恶烷在被寄生的红细胞中迅速积累，定位于滋养体和分裂体的消化液泡相关的中性脂质体内，并包围着发育中的分裂体膜。青蒿素预处理显著降低了中性脂质体的荧光标记，而铁螯合则增加了非特异性细胞质定位。为了进一步探讨内过氧化物对细胞脂质的影响，我们使用氧化敏感的BODIPY脂质探针来显示青蒿素诱导的过氧自由基在寄生虫膜中的存在。暴露于青蒿素的寄生虫的脂质提取物含有更多的游离脂肪酸和一种新的胆固醇酯。细胞积累模式和对脂质的影响完全依赖于内过氧化物，因为缺乏内过氧化物部分的失活二恶烷类似物无法标记中性脂体或诱导氧化膜损伤。在寄生虫的消化液泡中，中性脂与血红素密切相关，促进血红素的形成。我们认为，三氧环青蒿素及其衍生物在中性脂质环境中被血红素-铁激活，在那里它们启动氧化反应，破坏寄生虫膜。
The antimalarial trioxanes, exemplified by the naturally occurring sesquiterpene lactone artemisinin and its semi-synthetic derivatives, contain an endoperoxide pharmacophore that lends tremendous potency against Plasmodium parasites. Despite decades of research, their mechanism of action remains unresolved. A leading model of anti-plasmodial activity hypothesizes that iron-mediated cleavage of the endoperoxide bridge generates cytotoxic drug metabolites capable of damaging cellular macromolecules. To probe the malarial targets of the endoperoxide drugs, we studied the distribution of fluorescent dansyl trioxane derivatives in living, intraerythrocytic-stage P. falciparum parasites using microscopic imaging. The fluorescent trioxanes rapidly accumulated in parasitized erythrocytes, localizing within digestive vacuole-associated neutral lipid bodies of trophozoites and schizonts, and surrounding the developing merozoite membranes. Artemisinin pre-treatment significantly reduced fluorescent labeling of neutral lipid bodies, while iron chelation increased non-specific cytoplasmic localization. To further explore the effects of endoperoxides on cellular lipids, we used an oxidation-sensitive BODIPY lipid probe to show the presence of artemisinin-induced peroxyl radicals in parasite membranes. Lipid extracts from artemisinin-exposed parasites contained increased amounts of free fatty acids and a novel cholesteryl ester. The cellular accumulation patterns and effects on lipids were entirely endoperoxide-dependent, as inactive dioxolane analogs lacking the endoperoxide moiety failed to label neutral lipid bodies or induce oxidative membrane damage. In the parasite digestive vacuole, neutral lipids closely associate with heme and promote hemozoin formation. We propose that the trioxane artemisinin and its derivatives are activated by heme-iron within the neutral lipid environment where they initiate oxidation reactions that damage parasite membranes.
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影响因子：
9.8
作者：
Bozdech, Zbynek;Llinas, Manuel;Pulliam, Brian Lee;Wong, Edith D;Zhu, Jingchun;DeRisi, Joseph L
通讯作者：
DeRisi, Joseph L
DOI：
10.1016/0035-9203(87)90003-4
发表时间：
1987-01-01
影响因子：
2.2
作者：
KRUNGKRAI, SR;YUTHAVONG, Y
通讯作者：
YUTHAVONG, Y
影响因子：
4.8
作者：
Bhisutthibhan, J;Pan, XQ;Meshnick, SR
通讯作者：
Meshnick, SR
DOI：
10.1073/pnas.0711067105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Elliott, David A.;McIntosh, Michael T.;Joiner, Keith A.
通讯作者：
Joiner, Keith A.
影响因子：
64.8
作者：
Eckstein-Ludwig, U;Webb, RJ;Krishna, S
通讯作者：
Krishna, S