Department of Chemistry, New York University, New York, New York 10003, United States.
Biology Program, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates.
J Am Chem Soc. 2021 Mar 3;143(8):3086-3093. doi: 10.1021/jacs.0c09967. Epub 2021 Feb 18.
An interruption in Aβ homeostasis leads to the deposit of neurotoxic amyloid plaques and is associated with Alzheimer's disease. A supramolecular strategy based on the assembly of peptidomimetic agents into functional vesicles has been conceived for the simultaneous inhibition of Aβ fibrillation and expedited clearance of Aβ aggregates. Tris-pyrrolamide peptidomimetic, ADH-353, contains one hydrophobic -butyl and two hydrophilic -propylamine side chains and readily forms vesicles under physiological conditions. These vesicles completely rescue both mouse neuroblastoma N2a and human neuroblastoma SH-SY5Y cells from the cytotoxicity that follows from Aβ misfolding likely in mitochondria. Biophysical studies, including confocal imaging, demonstrate the biocompatibility and selectivity of the approach toward this aberrant protein assembly in cellular milieu.
Aβ 平衡的中断会导致神经毒性淀粉样斑块的沉积，并与阿尔茨海默病有关。基于将肽模拟物组装成功能性囊泡的超分子策略，已经被设想用于同时抑制 Aβ 纤维形成和加速 Aβ 聚集物的清除。三吡咯酰胺肽模拟物 ADH-353 含有一个疏水性 -丁基和两个亲水性 -丙胺侧链，在生理条件下很容易形成囊泡。这些囊泡完全挽救了 Aβ 错误折叠后导致的来自于小鼠神经母细胞瘤 N2a 和人神经母细胞瘤 SH-SY5Y 细胞的细胞毒性，可能是在线粒体中。包括共聚焦成像在内的生物物理研究表明，该方法在细胞环境中对这种异常蛋白组装具有生物相容性和选择性。
