Sonzini Silvia, Stanyon Helen F, Scherman Oren A
Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Phys Chem Chem Phys. 2017 Jan 4;19(2):1458-1465. doi: 10.1039/c6cp06765d.
Amyloid β is one of the peptides involved in the onset of Alzheimer's disease, yet the structure of the toxic species and its underlying mechanism remain elusive on account of the dynamic nature of the Aβ oligomerisation process. While it has been reported that incubation of Amyloid β (1-42) sequences (Aβ42) lead to formation of aggregates that vary in morphology and toxicity, we demonstrate that addition of a discrete macrocyclic host molecule, cucurbit[8]uril (CB[8]), substantially reduces toxicity in the neuronal cell line SH-SY5Y. The macrocycle preferentially targets Phe residues in Aβ42 complexing them in a 2 : 1 fashion in neighboring peptide strands. A small but significant structural 'switch' occurs, which induces an increased aggregation rate, suggesting a different cell-uptake mechanism for Aβ42 in the presence of CB[8]. Dramatically increasing the rate of Aβ42 aggregation with CB[8] bypasses the toxic, oligomeric state offering an alternative approach to counter Alzheimer's disease.
淀粉样蛋白β是参与阿尔茨海默病发病过程的肽段之一，但由于Aβ寡聚化过程的动态性质，有毒物种的结构及其潜在机制仍然难以捉摸。虽然有报道称，淀粉样蛋白β（1-42）序列（Aβ42）的孵育会导致形成形态和毒性各异的聚集体，但我们证明，添加一种离散的大环主体分子葫芦[8]脲（CB[8]）可显著降低神经母细胞瘤细胞系SH-SY5Y中的毒性。大环优先靶向Aβ42中的苯丙氨酸残基，以2∶1的方式在相邻肽链中将它们络合。发生了一个小而显著的结构“转变”，这导致聚集速率增加，表明在存在CB[8]的情况下，Aβ42的细胞摄取机制不同。用CB[8]显著提高Aβ42的聚集速率可绕过有毒的寡聚状态，为对抗阿尔茨海默病提供了一种替代方法。
