Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, NL-1081 HV Amsterdam, the Netherlands.
Mol Microbiol. 2011 Jan;79(1):94-108. doi: 10.1111/j.1365-2958.2010.07435.x. Epub 2010 Nov 5.
Awareness is growing that drug target validation should involve systems analysis of cellular networks. There is less appreciation, though, that the composition of networks may change in response to drugs. If the response is homeostatic (e.g. through upregulation of the target protein), this may neutralize the inhibitory effect. In this scenario the effect on cell growth and survival would be less than anticipated based on affinity of the drug for its target. Glycolysis is the sole free-energy source for the deadly parasite Trypanosoma brucei and is therefore a possible target pathway for anti-trypanosomal drugs. Plasma-membrane glucose transport exerts high control over trypanosome glycolysis and hence the transporter is a promising drug target. Here we show that at high inhibitor concentrations, inhibition of trypanosome glucose transport causes cell death. Most interestingly, sublethal concentrations initiate a domino effect in which network adaptations enhance inhibition. This happens via (i) metabolic control exerted by the target protein, (ii) decreases in mRNAs encoding the target protein and other proteins in the same pathway, and (iii) partial differentiation of the cells leading to (low) expression of immunogenic insect-stage coat proteins. We discuss how these 'anti-homeostatic' responses together may facilitate killing of parasites at an acceptable drug dosage.
人们越来越意识到，药物靶点验证应该涉及细胞网络的系统分析。然而，人们对网络的组成可能会因药物而发生变化的认识还不够。如果这种反应是动态平衡的（例如，通过靶蛋白的上调），这可能会中和抑制作用。在这种情况下，基于药物对其靶标的亲和力，药物对细胞生长和存活的影响将小于预期。糖酵解是致命寄生虫布鲁氏锥虫的唯一自由能来源，因此是抗锥虫药物的一个可能的靶点途径。质膜葡萄糖转运对锥虫糖酵解施加高度控制，因此转运蛋白是一个有前途的药物靶点。在这里，我们表明在高抑制剂浓度下，抑制锥虫葡萄糖转运会导致细胞死亡。最有趣的是，亚致死浓度会引发级联效应，其中网络适应会增强抑制作用。这是通过（i）靶蛋白施加的代谢控制，（ii）编码靶蛋白和同一途径中的其他蛋白质的 mRNA 减少，以及（iii）细胞的部分分化导致（低）表达免疫原性昆虫阶段外壳蛋白。我们讨论了这些“反动态平衡”反应如何共同促进在可接受的药物剂量下杀死寄生虫。
