HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome bc1 Complex
HDQ, a Potent Inhibitor of Plasmodium falciparum Proliferation, Binds to the Quinone Reduction Site of the Cytochrome bc1 Complex
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DOI：
10.1128/aac.00486-12
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发表时间：
2012-07-01
影响因子：
4.9
通讯作者：
Meunier, Brigitte
中科院分区：
文献类型：
--
作者：
Vallieres, Cindy;Fisher, Nicholas;Meunier, Brigitte
线粒体bc（1）复合物是一种多亚基酶，催化电子从泛醇转移到细胞色素c，并结合质子跨线粒体内膜的矢量易位。复合物含有两个不同的醌结合位点，bc（1）复合物的醌氧化位点（Q（o））和醌还原位点（Q（i）），位于细胞色素B内膜的相对两侧。Q（o）位点抑制剂，如阿托伐醌（atovaquone），对恶性疟原虫bc（1）复合物有活性，已被开发和配制成抗疟疾药物。不幸的是，Q（o）位点的单点突变可以迅速使阿托伐醌无效。需要开发能够避免与阿托伐醌交叉耐药性的药物。在这里，我们报告了一种有效的恶性疟原虫增殖抑制剂，1-羟基-2-十二烷基-4-（1H）喹诺酮（HDQ）的作用模式。我们发现，寄生虫bc（1）复杂的控制和阿托伐醌耐药菌株，抑制亚微摩尔浓度的HDQ，表明这两种药物有不同的目标内的复杂。然后通过使用酵母模型确定HDQ的结合位点。将点突变引入Q（i）位点，即G33 A、H204 Y、M221 Q和K228 M，显著降低HDQ抑制。相反，Q（o）位点的已知抑制剂耐药突变不会导致HDQ耐药。这项研究使用HDQ作为原理验证抑制剂，表明bc（1）复合物的Q（i）位点是抗疟药物开发的可行靶点。
The mitochondrial bc(1) complex is a multisubunit enzyme that catalyzes the transfer of electrons from ubiquinol to cytochrome c coupled to the vectorial translocation of protons across the inner mitochondrial membrane. The complex contains two distinct quinone-binding sites, the quinol oxidation site of the bc(1) complex (Q(o)) and the quinone reduction site (Q(i)), located on opposite sides of the membrane within cytochrome b. Inhibitors of the Q(o) site such as atovaquone, active against the bc(1) complex of Plasmodium falciparum, have been developed and formulated as antimalarial drugs. Unfortunately, single point mutations in the Q(o) site can rapidly render atovaquone ineffective. The development of drugs that could circumvent cross-resistance with atovaquone is needed. Here, we report on the mode of action of a potent inhibitor of P. falciparum proliferation, 1-hydroxy-2-dodecyl-4-(1H)quinolone (HDQ). We show that the parasite bc(1) complex-from both control and atovaquone-resistant strains-is inhibited by submicromolar concentrations of HDQ, indicating that the two drugs have different targets within the complex. The binding site of HDQ was then determined by using a yeast model. Introduction of point mutations into the Q(i) site, namely, G33A, H204Y, M221Q, and K228M, markedly decreased HDQ inhibition. In contrast, known inhibitor resistance mutations at the Q(o) site did not cause HDQ resistance. This study, using HDQ as a proof-of-principle inhibitor, indicates that the Q(i) site of the bc(1) complex is a viable target for antimalarial drug development.