A strategy for designing inhibitors of beta-amyloid toxicity
A strategy for designing inhibitors of beta-amyloid toxicity
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DOI：
10.1074/jbc.271.47.29525
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发表时间：
1996-11-22
影响因子：
4.8
通讯作者：
Murphy, RM
中科院分区：
文献类型：
--
作者：
Ghanta, J;Shen, CL;Murphy, RM
β-淀粉样肽是阿尔茨海默病斑块的主要蛋白质成分。当聚集成淀粉样原纤维时，该肽对神经元细胞有毒。这里描述了一种设计 β-淀粉样蛋白毒性抑制剂的方法；在该策略中，与β-淀粉样蛋白特异性相互作用的识别元件与破坏元件相结合，从而改变β-淀粉样蛋白聚集途径。报道了这种抑制剂的合成、生物物理特征和生物活性。这种原型抑制剂由β-淀粉样肽的残基15-25组成，设计用作识别元件，与寡聚赖氨酸破坏元件连接。该抑制剂不会改变 β-淀粉样蛋白的表观二级结构，也不会阻止其聚集；相反，它会导致聚集动力学和聚集体的高阶结构特征发生变化。这些作用的证据包括原纤维形态的变化和硫黄素 T 荧光的减少。除了对 β-淀粉样蛋白聚集体的物理性质的影响外，该抑制剂还完全阻断了 β-淀粉样蛋白对 PC-12 细胞的毒性。总之，这些数据表明，这种设计β-淀粉样蛋白毒性抑制剂的一般策略是有效的。值得注意的是，这些结果表明，完全破坏淀粉样蛋白原纤维的形成对于消除毒性来说并不是必需的。
beta-Amyloid peptide is the major protein component of Alzheimer's plaques. When aggregated into amyloid fibrils, the peptide is toxic to neuronal cells. Here, an approach to the design of inhibitors of beta-amyloid toxicity is described; in this strategy, a recognition element, which interacts specifically with beta-amyloid, is combined with a disrupting element, which alters beta-amyloid aggregation pathways. The synthesis, biophysical characterization, and biological activity of such an inhibitor is reported, This prototype inhibitor is composed of residues 15-25 of beta-amyloid peptide, designed to function as the recognition element, linked to an oligolysine disrupting element. The inhibitor does not alter the apparent secondary structure of beta-amyloid nor prevent its aggregation; rather, it causes changes in aggregation kinetics and higher order structural characteristics of the aggregate. Evidence for these effects includes changes in fibril morphology and a reduction in thioflavin T fluorescence, In addition to its influence on the physical properties of beta-amyloid aggregates, the inhibitor completely blocks beta-amyloid toxicity to PC-12 cells. Together, these data suggest that this general strategy for design of beta-amyloid toxicity inhibitors is effective, Significantly, these results demonstrate that complete disruption of amyloid fibril formation is not necessary for abrogation of toxicity.