Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity.
Low molecular weight, non-peptidic agonists of TrkA receptor with NGF-mimetic activity.
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DOI：
10.1038/cddis.2012.80
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发表时间：
2012-07-05
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
利用神经营养因子的生物活性是医疗目的所需要的，但其蛋白质本质上具有不利的药代动力学特性。在这里，我们报道了一类具有模拟神经生长因子（NGF）特性的新型低分子量非肽化合物的合成和生物学特性。MT2是一种代表性的化合物，在纳米摩尔浓度下与ngf敏感细胞上的Trk（原肌球蛋白激酶受体）链结合，并诱导TrkA自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增加细胞外信号调节的激酶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p38丝裂原激活的蛋白激酶的激活，维持血清饥饿的PC12或RDG细胞的存活，并促进其分化。然而，这种反应的强度是不均匀的，因为NGF和MT2同样具有维持生存的能力，而模仿物诱导分化的表达水平明显较低。对MT2诱导的TrkA自磷酸化模式的分析显示，酪氨酸（Tyr）490强烈激活，Tyr785和Tyr674/675有限激活，这与观察到的功能分化一致。与此一致的是，在缺乏ngf的大鼠阿尔茨海默病海马神经元模型中，MT2可以纠正生化异常并维持细胞存活。因此，NGF模拟物可能会揭示神经生物学中有趣的研究工具，以及有前途的候选药物。
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 kinase1/2 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.
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影响因子：
4.7
作者：
de Pablo, Yolanda;Perez-Garcia, M. Jose;Lloveral, Marta
通讯作者：
Lloveral, Marta
DOI：
10.1073/pnas.0904998106
发表时间：
2009-07-07
影响因子：
11.1
作者：
Matrone, C.;Marolda, R.;Calissano, P.
通讯作者：
Calissano, P.
影响因子：
20.1
作者：
Meloni M;Caporali A;Graiani G;Lagrasta C;Katare R;Van Linthout S;Spillmann F;Campesi I;Madeddu P;Quaini F;Emanueli C
通讯作者：
Emanueli C
影响因子：
5.6
作者：
ABAGYAN, R;TOTROV, M
通讯作者：
TOTROV, M
影响因子：
4.8
作者：
Kaiser, RA;Bueno, OF;Molkentin, JD
通讯作者：
Molkentin, JD