A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor
A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor
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DOI：
10.1021/cb200105d
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发表时间：
2011-11-01
影响因子：
4
通讯作者：
Winzeler, Elizabeth A.
中科院分区：
文献类型：
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作者：
Nam, Tae-gyu;McNamara, Case W.;Winzeler, Elizabeth A.
癸氧喹酯对体外血液阶段恶性疟原虫（人类疟疾的病原体）具有单位数纳摩尔活性。在体外进化的癸氧喹酯耐药寄生虫和随后的比较基因组分析的药物敏感的亲本菌株显示的电阻是由两个非同义的单核苷酸多态性的基因编码细胞色素B。产生的氨基酸突变A122 T和Y126 C位于细胞色素B的泛喹啉结合口袋的螺旋C内，细胞色素bc（1）复合物的必需亚基。与其他细胞色素bc（1）抑制剂一样，如阿托伐醌，癸氧喹酯对体外肝脏阶段约氏疟原虫具有低纳摩尔活性，当以50 mg kg（-1）给药感染小鼠时，可提供部分预防保护。此外，转基因。表达酵母二氢乳清酸脱氢酶的寄生虫对癸氧喹酯的敏感性低200倍以上，这提供了该药物抑制寄生虫线粒体电子传递链的额外证据。重要的是，癸氧喹酯对一组阿托伐醌抗性寄生虫表现出有限的交叉抗性，所述寄生虫进化为在细胞色素B中具有各种突变。分子对接研究揭示了这种差异的基础，其中这两种抑制剂被证明具有明显不同的细胞色素B的泛喹啉结合位点内的结合模式。
Decoquinate has single-digit nanomolar activity against in vitro blood stage Plasmodium falciparum parasites, the causative agent of human malaria. In vitro evolution of decoquinate-resistant parasites and subsequent comparative genomic analysis to the drug sensitive parental strain revealed resistance was conferred by two nonsynonymous single nucleotide polymorphisms in the gene encoding cytochrome b. The resultant amino acid mutations, A122T and Y126C, reside within helix C in the ubiquinol-binding pocket of cytochrome b, an essential subunit of the cytochrome bc(1) Complex. As with other cytochrome bc(1) inhibitors, such as atovaquone, decoquinate has low nanomolar activity against in vitro liver stage P. yoelii and provides partial prophylaxis protection when administered to infected mice at 50 mg kg(-1). In addition, transgenic. parasites expressing yeast dihydroorotate dehydrogenase are >200 fold less sensitive to decoquinate, which provides additional evidence that this drug inhibits the parasite's mitochondrial electron transport chain Importantly, decoquinate exhibits limited cross resistance to a panel of atovaquone-resistant parasites evolved to harbor various mutations in-cytochrome b. The basis for this difference was revealed by molecular docking studies, in which both of these inhibitors were shown to have distinctly different modes of binding within the ubiquinol-binding site of cytochrome b.