On the molecular mechanism of chloroquine's antimalarial action
On the molecular mechanism of chloroquine's antimalarial action
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DOI：
10.1073/pnas.93.21.11865
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发表时间：
1996-10-15
影响因子：
11.1
通讯作者：
Goldberg, DE
中科院分区：
文献类型：
--
作者：
Sullivan, DJ;Gluzman, IY;Goldberg, DE
氯喹被认为是通过阻止在疟原虫消化泡中血红蛋白的蛋白水解过程中释放的有毒血红素的聚合来发挥其抗疟作用。这种封锁的机制尚未建立。我们培养的寄生虫与亚抑制剂量的[H-3]氯喹和[H-3]奎尼丁。这些[H-3]喹啉化合物成为与疟原虫色素的电子显微镜放射自显影和亚细胞分级评估。在体外，结合[H-3]喹啉抑制剂的疟原虫色素链依赖于血红素底物的加入。这些数据反对先前的结论，缺乏喹啉协会与疟原虫色素，解释夸大的积累喹啉在疟原虫消化泡，并建议喹啉血红素复合物纳入不断增长的聚合物终止链延伸，阻止进一步螯合有毒血红素。
Chloroquine is thought to exert its antimalarial effect by preventing the polymerization of toxic heme released during proteolysis of hemoglobin in the Plasmodium digestive vacuole. The mechanism of this blockade has not been established. We incubated cultured parasites with subinhibitory doses of [H-3]chloroquine and [H-3]quinidine. These [H-3]quinoline compounds became associated with hemozoin as assessed by electron microscope autoradiography and subcellular fractionation. In vitro, binding of [H-3]quinoline inhibitors to the hemozoin chain depended on the addition of heme substrate. These data counter previous conclusions regarding the lack of quinoline association with hemozoin, explain the exaggerated accumulation of quinolines in the Plasmodium digestive vacuole, and suggest that a quinoline-heme complex incorporates into the growing polymer to terminate chain extension, blocking further sequestration of toxic heme.