Targeting pathogen metabolism without collateral damage to the host.
Targeting pathogen metabolism without collateral damage to the host.
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DOI：
10.1038/srep40406
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发表时间：
2017-01-13
影响因子：
4.6
通讯作者：
Bakker BM
中科院分区：
文献类型：
--
作者：
Haanstra JR;Gerding A;Dolga AM;Sorgdrager FJH;Buist-Homan M;du Toit F;Faber KN;Holzhütter HG;Szöör B;Matthews KR;Snoep JL;Westerhoff HV;Bakker BM
由于生物体之间的许多蛋白质非常相似，开发能够抑制致病细胞（例如癌细胞或寄生虫）而不对健康细胞或宿主细胞造成附带损害的药物变得复杂。然而，由于靶细胞和宿主的生化反应网络之间存在细微的数量差异，药物可以限制一种生物体中相同基本过程的流量。我们确定了这种“基于网络”的药物选择性的精确标准，这可以作为结构差异的替代或添加剂。我们结合计算和实验方法比较昏睡病的病原体，布氏锥虫，与人类红细胞的能量代谢，并确定葡萄糖转运和甘油醛-3-磷酸脱氢酶作为最具选择性的抗寄生虫的目标。在一种新的寄生虫-红细胞共培养系统中，实验验证了计算预测。葡萄糖转运抑制剂杀死锥虫而不杀死红细胞、神经元或肝细胞。
The development of drugs that can inactivate disease-causing cells (e.g. cancer cells or parasites) without causing collateral damage to healthy or to host cells is complicated by the fact that many proteins are very similar between organisms. Nevertheless, due to subtle, quantitative differences between the biochemical reaction networks of target cell and host, a drug can limit the flux of the same essential process in one organism more than in another. We identified precise criteria for this ‘network-based’ drug selectivity, which can serve as an alternative or additive to structural differences. We combined computational and experimental approaches to compare energy metabolism in the causative agent of sleeping sickness, Trypanosoma brucei, with that of human erythrocytes, and identified glucose transport and glyceraldehyde-3-phosphate dehydrogenase as the most selective antiparasitic targets. Computational predictions were validated experimentally in a novel parasite-erythrocytes co-culture system. Glucose-transport inhibitors killed trypanosomes without killing erythrocytes, neurons or liver cells.
影响因子：
3.8
作者：
Jennings, M L;Solomon, A K
通讯作者：
Solomon, A K