University of Groningen, University Medical Center Groningen, Department of Pediatrics and Systems Biology Centre for Energy Metabolism and Ageing, Center for Liver, Digestive and Metabolic Diseases, Groningen, The Netherlands.
Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, VU University, Amsterdam, The Netherlands.
Sci Rep. 2017 Jan 13;7:40406. doi: 10.1038/srep40406.
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.
开发能够使致病细胞（如癌细胞或寄生虫）失活而不损伤健康细胞或宿主细胞的药物，这一过程很复杂，因为许多蛋白质在生物体之间非常相似。然而，由于靶细胞和宿主的生化反应网络之间存在细微的、定量的差异，一种药物可以限制同一关键过程在一个生物体中的通量，而不是在另一个生物体中的通量。我们确定了这种“基于网络”的药物选择性的精确标准，它可以作为结构差异的替代或补充。我们结合计算和实验方法，比较了昏睡病病原体布氏锥虫和人红细胞的能量代谢，并确定葡萄糖转运和甘油醛-3-磷酸脱氢酶是最具选择性的抗寄生虫靶点。在一种新的寄生虫-红细胞共培养系统中，计算预测得到了实验验证。葡萄糖转运抑制剂可以杀死锥虫而不杀死红细胞、神经元或肝细胞。
