Ruan Benfang, Pong Kevin, Jow Flora, Bowlby Mark, Crozier Robert A, Liu Danni, Liang Shi, Chen Yi, Mercado Mary Lynn, Feng Xidong, Bennett Frann, von Schack David, McDonald Leonard, Zaleska Margaret M, Wood Andrew, Reinhart Peter H, Magolda Ronald L, Skotnicki Jerauld, Pangalos Menelas N, Koehn Frank E, Carter Guy T, Abou-Gharbia Magid, Graziani Edmund I
Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA.
Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):33-8. doi: 10.1073/pnas.0710424105. Epub 2007 Dec 27.
Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show that modification of rapamycin at the mammalian target of rapamycin (mTOR) binding region yields immunophilin ligands, WYE-592 and ILS-920, with potent neurotrophic activities in cortical neuronal cultures, efficacy in a rodent model for ischemic stroke, and significantly reduced immunosuppressive activity. Surprisingly, both compounds showed higher binding selectivity for FKBP52 versus FKBP12, in contrast to previously reported immunophilin ligands. Affinity purification revealed two key binding proteins, the immunophilin FKBP52 and the beta1-subunit of L-type voltage-dependent Ca(2+) channels (CACNB1). Electrophysiological analysis indicated that both compounds can inhibit L-type Ca(2+) channels in rat hippocampal neurons and F-11 dorsal root ganglia (DRG)/neuroblastoma cells. We propose that these immunophilin ligands can protect neurons from Ca(2+)-induced cell death by modulating Ca(2+) channels and promote neurite outgrowth via FKBP52 binding.
雷帕霉素是一种免疫抑制性亲免素配体，据报道具有神经营养活性。我们发现，在雷帕霉素的哺乳动物雷帕霉素靶蛋白（mTOR）结合区域进行修饰可产生亲免素配体WYE - 592和ILS - 920，它们在皮质神经元培养物中具有强大的神经营养活性，在啮齿动物缺血性中风模型中有效，并且免疫抑制活性显著降低。令人惊讶的是，与先前报道的亲免素配体相比，这两种化合物对FKBP52的结合选择性高于FKBP12。亲和纯化揭示了两种关键结合蛋白，亲免素FKBP52和L型电压依赖性Ca(2+)通道（CACNB1）的β1亚基。电生理分析表明，这两种化合物均可抑制大鼠海马神经元和F - 11背根神经节（DRG）/神经母细胞瘤细胞中的L型Ca(2+)通道。我们提出，这些亲免素配体可通过调节Ca(2+)通道保护神经元免受Ca(2+)诱导的细胞死亡，并通过与FKBP52结合促进神经突生长。
Zotero 插件