Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death
Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death
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DOI：
10.1523/jneurosci.3547-05.2006
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发表时间：
2006-05-17
影响因子：
5.3
通讯作者：
Longo, Frank M.
中科院分区：
文献类型：
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作者：
Massa, Stephen M.;Xie, Youmei;Longo, Frank M.
研究表明，神经营养因子与p75（NTR）结合可以在缺乏Trk的情况下促进细胞存活（原肌球蛋白相关激酶）受体，以及最近的结构数据表明NGF可以以单价方式结合p75（NTR），小分子p75（NTR）一个药效团被设计用来捕捉一个被选择的结构和物理化学特征，将已知与p75相互作用的神经营养蛋白结构域（NTR）应用于小分子文库的计算机筛选。小的，非肽，单体化合物被确定与p75（NTR）相互作用。在显示对神经营养因子的营养反应的细胞中，化合物通过p75（NTR）依赖性机制促进存活信号传导。在对神经营养素原诱导的死亡敏感的细胞中，化合物不诱导细胞凋亡，但抑制神经营养素原介导的死亡。这些研究确定了一系列独特的p75（NTR）行为，这些行为可能是由孤立的受体配体引起的，并建立了几种新的治疗线索。
Studies showing that neurotrophin binding to p75(NTR) can promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating that NGF may bind to p75(NTR) in a monovalent manner, raise the possibility that small molecule p75(NTR) ligands that positively regulate survival might be found. Apharmacophore designed to capture selected structural and physical chemical features of a neurotrophin domain known to interact with p75(NTR) was applied to in silico screening of small molecule libraries. Small, nonpeptide, monomeric compounds were identified that interact with p75(NTR). In cells showing trophic responses to neurotrophins, the compounds promoted survival signaling through p75(NTR)-dependent mechanisms. In cells susceptible to proneurotrophin-induced death, compounds did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify a unique range of p75(NTR) behaviors that can result from isolated receptor liganding and establish several novel therapeutic leads.