Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs
Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs
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DOI：
10.1128/aac.00850-16
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发表时间：
2016-08-01
影响因子：
4.9
通讯作者：
Landfear, Scott M.
中科院分区：
文献类型：
--
作者：
Ortiz, Diana;Forquer, Isaac;Landfear, Scott M.
类内皮素喹诺酮类化合物是恶性疟原虫和刚地弓形虫细胞色素bc（1）的特异性抑制剂，有望成为新型抗寄生虫药物。为了确定利什曼原虫的线粒体电子传递链是否可以类似地用于药物开发，我们研究了134种结构不同的ELQ的活性。一组ELQ对墨西哥利什曼原虫和L. donovani，50%抑制浓度（IC（50））在低微摩尔范围内，但结构相似的羟基萘醌丁帕伐醌是迄今为止最有效的电子传递，ATP的生产，和细胞内无鞭毛体生长的抑制剂。因此，细胞色素bc（1）是新型抗利什曼病药物的一个有希望的靶点，进一步改进丁帕伐醌支架是开发增强治疗药物的必要条件。
Endochin-like quinolones (ELQs) are potent and specific inhibitors of cytochrome bc(1) from Plasmodium falciparum and Toxoplasma gondii and show promise for novel antiparasitic drug development. To determine whether the mitochondrial electron transport chain of Leishmania parasites could be targeted similarly for drug development, we investigated the activity of 134 structurally diverse ELQs. A cohort of ELQs was selectively toxic to amastigotes of Leishmania mexicana and L. donovani, with 50% inhibitory concentrations (IC(50)s) in the low micromolar range, but the structurally similar hydroxynaphthoquinone buparvaquone was by far the most potent inhibitor of electron transport, ATP production, and intracellular amastigote growth. Cytochrome bc(1) is thus a promising target for novel antileishmanial drugs, and further improvements on the buparvaquone scaffold are warranted for development of enhanced therapeutics.