Stoichiometric Inhibition of Amyloid β-Protein Aggregation with Peptides Containing Alternating α,α-Disubstituted Amino Acids

化学 圆二色性 纤维 球状蛋白 氨基酸 化学计量学 蛋白质二级结构 结晶学 淀粉样蛋白(真菌学) 测试表 生物物理学 透射电子显微镜 淀粉样纤维 立体化学 生物化学 淀粉样β 有机化学 化学工程 医学 无机化学 疾病 病理 工程类 生物
作者
Marcus A. Etienne,Jed P. Aucoin,Yanwen Fu,Robin L. McCarley,Robert E. Hammer
出处
期刊:Journal of the American Chemical Society [American Chemical Society]
卷期号:128 (11): 3522-3523 被引量:79
标识
DOI:10.1021/ja0600678
摘要

We have prepared two peptides based on the hydrophobic core (Lys-Leu-Val-Phe-Phe) of amyloid beta-protein (Abeta) that contain alpha,alpha-disubstituted amino acids at alternating positions, but differ in the positioning of the oligolysine chain (AMY-1, C-terminus; AMY-2, N-terminus). We have studied the effects of AMY-1 and AMY-2 on the aggregation of Abeta and find that, at stoichiometric concentrations, both peptides completely stop Abeta fibril growth. Equimolar mixtures of AMY-1 and Abeta form only globular aggregates as imaged by scanning force microscopy and transmission electron microscopy. These samples show no signs of protofibrillar or fibrillar material even after prolonged periods of time (4.5 months). Also, 10 mol % of AMY-1 prevents Abeta self-assembly for long periods of time; aged samples (4.5 months) show only a few protofibrillar or fibrillar aggregates. Circular dichroism spectroscopy of equimolar mixtures of AMY-1 and Abeta show that the secondary structure of the mixture changes over time and progresses to a predominantly beta-sheet structure, which is consistent with the design of these inhibitors preferring a sheet-like conformation. Changing the position of the charged tail on the peptide, AMY-2 interacts with Abeta differently in that equimolar mixtures form large ( approximately 1 mum) globular aggregates which do not progress to fibrils, but precipitate out of solution. The differences in the aggregation mediated by the two peptides is discussed in terms of a model where the inhibitors act as cosurfactants that interfere with the native ability of Abeta to self-assemble by disrupting hydrophobic interactions either at the C-terminus or N-terminus of Abeta.
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