Department of Chemistry 'Ugo Schiff', University of Firenze, Via della Lastruccia 13, Sesto Fiorentino, I-50019 Firenze, Italy.
Cell Death Dis. 2012 Sep 6;3(9):e389. doi: 10.1038/cddis.2012.129.
Exploitation of the biologic activity of neurotrophins is desirable for medical purposes, but their protein nature intrinsically bears adverse pharmacokinetic properties. Here, we report synthesis and biologic characterization of a novel class of low molecular weight, non-peptidic compounds with NGF (nerve growth factor)-mimetic properties. MT2, a representative compound, bound to Trk (tropomyosin kinase receptor)A chain on NGF-sensitive cells, as well as in cell-free assays, at nanomolar concentrations and induced TrkA autophosphorylation and receptor-mediated internalization. MT2 binding involved at least two amino-acid residues within TrkA molecule. Like NGF, MT2 increased phosphorylation of extracellular signal-regulated kinase 1/2 and Akt proteins and production of MKP-1 phosphatase (dual specificity phosphatase 1), modulated p38 mitogen-activated protein kinase activation,sustained survival of serum-starved PC12 or RDG cells, and promoted their differentiation. However, the intensity of such responses was heterogenous, as the ability of maintaining survival was equally possessed by NGF and MT2, whereas the induction of differentiation was expressed at definitely lower levels by the mimetic. Analysis of TrkA autophosphorylation patterns induced by MT2 revealed a strong tyrosine (Tyr)490 and a limited Tyr785 and Tyr674/675 activation, findings coherent with the observed functional divarication. Consistently, in an NGF-deprived rat hippocampal neuronal model of Alzheimer Disease, MT2 could correct the biochemical abnormalities and sustain cell survival. Thus, NGF mimetics may reveal interesting investigational tools in neurobiology, as well as promising drug candidates.
神经生长因子（nerve growth factor，NGF）等神经营养因子的生物活性被广泛用于医疗目的，但由于其蛋白本质，内在地具有不良的药代动力学特性。在这里，我们报告了一类新型低分子量、非肽类化合物的合成和生物学特征，这些化合物具有 NGF（神经生长因子）模拟特性。MT2 是一种代表性化合物，能够以纳摩尔浓度结合 NGF 敏感细胞上的 Trk（原肌球蛋白激酶受体）A 链，以及在无细胞测定中，与 TrkA 结合，并诱导 TrkA 自身磷酸化和受体介导的内化。MT2 结合涉及 TrkA 分子内至少两个氨基酸残基。与 NGF 一样，MT2 增加了细胞外信号调节激酶 1/2 和 Akt 蛋白的磷酸化以及 MKP-1 磷酸酶（双特异性磷酸酶 1）的产生，调节了 p38 丝裂原活化蛋白激酶的激活，维持了血清饥饿的 PC12 或 RDG 细胞的存活，并促进了它们的分化。然而，这种反应的强度是不同的，因为 NGF 和 MT2 同样具有维持存活的能力，而模拟物诱导分化的能力则明显较低。分析 MT2 诱导的 TrkA 自身磷酸化模式表明，强烈的酪氨酸（Tyr）490 和有限的 Tyr785 和 Tyr674/675 激活，这与观察到的功能差异是一致的。一致地，在阿尔茨海默病（Alzheimer Disease）的 NGF 剥夺大鼠海马神经元模型中，MT2 可以纠正生化异常并维持细胞存活。因此，NGF 模拟物可能在神经生物学中揭示出有趣的研究工具，同时也是有前途的药物候选物。
