Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, California 94158, United States.
J Med Chem. 2012 Nov 8;55(21):8997-9008. doi: 10.1021/jm3008618. Epub 2012 Oct 5.
An attractive strategy to treat proteinopathies (diseases caused by malformed or misfolded proteins) is to restore protein function by inducing proper three-dimensional structure. We hypothesized that this approach would be effective in reversing the detrimental effects of apolipoprotein (apo) E4, the major allele that significantly increases the risk of developing Alzheimer's disease and other neurodegenerative disorders. ApoE4's detrimental effects result from its altered protein conformation ("domain interaction"), making it highly susceptible to proteolytic cleavage and the generation of neurotoxic fragments. Here, we review apoE structure and function and how apoE4 causes neurotoxicity, and describe the identification of potent small-molecule-based "structure correctors" that induce proper apoE4 folding. SAR studies identified a series of small molecules that significantly reduced apoE4's neurotoxic effects in cultured neurons and a series that reduced apoE4 fragment levels in vivo, providing proof-of-concept for our approach. Structure-corrector-based therapies could prove to be highly effective for the treatment of many protein-misfolding diseases.
治疗蛋白质病（由畸形或错误折叠的蛋白质引起的疾病）的一种有吸引力的策略是通过诱导适当的三维结构来恢复蛋白质功能。我们假设这种方法在逆转载脂蛋白 (apo) E4 的有害影响方面将是有效的，apoE4 是显著增加患阿尔茨海默病和其他神经退行性疾病风险的主要等位基因。ApoE4 的有害影响是由于其改变的蛋白质构象（“结构域相互作用”），使其极易受到蛋白水解切割和产生神经毒性片段的影响。在这里，我们回顾了 apoE 的结构和功能，以及 apoE4 如何引起神经毒性，并描述了鉴定强效基于小分子的“结构校正剂”的方法，这些校正剂可诱导适当的 apoE4 折叠。SAR 研究鉴定了一系列小分子，这些小分子可显著降低培养神经元中的 apoE4 神经毒性作用，并且一系列小分子可降低体内 apoE4 片段水平，为我们的方法提供了概念验证。基于结构校正剂的治疗方法可能被证明对治疗许多蛋白质错误折叠疾病非常有效。
