Polymorphism in the Plasmodium falciparum chloroquine-resistance transporter protein links verapamil enhancement of chloroquine sensitivity with the clinical efficacy of amodiaquine.
Polymorphism in the Plasmodium falciparum chloroquine-resistance transporter protein links verapamil enhancement of chloroquine sensitivity with the clinical efficacy of amodiaquine.
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DOI：
10.1186/1475-2875-2-31
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发表时间：
2003-09-19
期刊：
影响因子：
3
通讯作者：
Warhurst DC
中科院分区：
文献类型：
--
作者：
Warhurst DC
氯喹积聚在红细胞内疟原虫的酸性消化液泡中，并阻止血红蛋白消化过程中释放的血红素的解毒。恶性疟原虫红细胞内生长阶段消化液泡膜中蛋白质 PfCRT 的变化对于抵抗力至关重要。 PfCRT 在酵母中表达，类似于阴离子通道。阴离子通道功能的抑制可以增加溶酶体内的pH值以减少碱性药物的进入，或者增强功能可以减少药物与目标血红素的相互作用。最重要的耐药相关变化是从带正电荷的赖氨酸 76 变为中性苏氨酸，这可以促进药物通过假定的通道流出。有人提出，维拉帕米的耐药逆转作用是由于与突变的 PfCRT 蛋白的疏水性结合，并取代了丢失的正电荷，从而排斥了 4-氨基喹啉阳离子的进入，从而部分恢复了敏感性。去乙基阿莫地喹是阿莫地喹的活性代谢物，具有显着的抗氯喹活性，其本身也可能产生类似的作用。分析了不同 CQ 抗性 PfCRT 序列中理化参数的变化，并检查了与 pfcrt 基因不同等位基因转染品系上药物活性的相关性。结果支持这样的观点，即 PfCRT 是一种通道，在耐药寄生虫中，可以允许氯喹从消化液泡中流出。氯喹/维拉帕米组合和去乙基阿地喹的活性均与 PfCRT 残基 72-76 的平均疏水性相关。这可能部分解释了南美首例耐氯喹疟疾病例中发现的对阿莫地喹的临床耐药性，并能够初步预测阿莫地喹对 PfCRT 新单倍型的临床活性。
Chloroquine accumulates in the acidic digestive vacuole of the intraerythrocytic malaria parasite, and prevents the detoxication of haematin released during haemoglobin digestion. Changes in protein PfCRT in the digestive vacuole membrane of growing intra-erythrocytic stages of Plasmodium falciparum are crucial for resistance. Expressed in yeast, PfCRT resembles an anion channel. Depressed anion channel function could increase intralysosomal pH to reduce entry of basic drug, or enhanced function could reduce drug interaction with target haematin. The most important resistance-associated change is from positively-charged lysine-76 to neutral threonine which could facilitate drug efflux through a putative channel. It has been proposed that the resistance-reversing effect of verapamil is due to hydrophobic binding to the mutated PfCRT protein, and replacement of the lost positive charge, which repels the access of 4-aminoquinoline cations, thus partially restoring sensitivity. Desethylamodiaquine, the active metabolite of amodiaquine, which has significant activity in chloroquine-resistance, may also act similarly on its own. Changes in physicochemical parameters in different CQ-resistant PfCRT sequences are analysed, and correlations with drug activity on lines transfected with different alleles of the pfcrt gene are examined. The results support the idea that PfCRT is a channel which, in resistant parasites, can allow efflux of chloroquine from the digestive vacuole. Activity of the chloroquine/verapamil combination and of desethylamodiaquine both correlate with the mean hydrophobicity of PfCRT residues 72-76. This may partly explain clinical-resistance to amodiaquine found in the first chloroquine-resistant malaria cases from South America and enables tentative prediction of amodiaquine's clinical activity against novel haplotypes of PfCRT.
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影响因子：
64.8
作者：
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通讯作者：
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