Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity.
Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity.
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与阿尔茨海默氏症、帕金森氏症和II型糖尿病（以及许多其他疾病）等疾病相关的淀粉样蛋白聚集的特征是从天然蛋白质向有序寡聚体和纤维过渡的各种令人困惑的富含β-片层的结构。β-结构的氨基酸序列的变化对开发用于研究各种淀粉样蛋白聚集体的β-折叠的模型系统提出了挑战。在这里，我们介绍了一个强大的β-折叠大环家族，可以作为一个平台，展示各种不同的淀粉样蛋白的七肽序列。我们已经定制了这些淀粉样蛋白β-折叠模拟物（ABSM）来拮抗各种淀粉样蛋白的聚集，从而降低淀粉样蛋白聚集体的毒性。我们描述了ABSM的结构和抑制特性，ABSM含有来自与阿尔茨海默病相关的Aβ的淀粉样蛋白生成肽、与透析相关的淀粉样变性相关的β2-微球蛋白、与帕金森病相关的α-突触核蛋白、与II型糖尿病相关的胰岛淀粉样蛋白多肽、人和酵母朊病毒蛋白以及形成神经元缠结的Tau。
The amyloid protein aggregation associated with diseases such as Alzheimer’s, Parkinson’s, and type II diabetes (among many others), features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibers. The variation in the amino acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from Aβ associated with Alzheimer’s disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson’s disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.
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