蛋白质错误折叠相关疾病的多肽药物研究进展

蛋白质和多肽发生错误折叠形成不可溶的淀粉样纤维的过程,与阿尔茨海默病、帕金森病等多种神经退行性疾病密切相关。这些疾病可导致认知能力下降以及运动缺陷等症状。虽然已有多种相关治疗方案处于临床试验中,但目前仍无明确有效的方法可治愈或长期减缓疾病的进展。探寻和研究抑制淀粉样聚集、识别并促进毒性聚集物清除的抑制剂分子是药物研发的重要策略之一。在不同类型的抑制剂中,多肽类抑制剂因具有高特异性、低毒性、多样性,以及修饰后的抗水解稳定性和血脑屏障通透性,有望成为候选药物分子。本文总结了针对阿尔茨海默病相关的Aβ和Tau蛋白以及帕金森病相关的α-synuclein蛋白淀粉样纤维化的多肽抑制剂研究进展。基于淀粉样纤维化核心序列及纤维核心结构进行合理设计,或通过随机筛选,均可获得多肽抑制剂。这些天然和非天然的多肽分子大多具有抑制淀粉样纤维化、解聚成熟纤维和降低细胞毒性的作用,其中一些多肽在退行性疾病动物模型实验中,显示出降低脑损伤和缓解认知及运动障碍的效果。这些研究揭示了多肽作为蛋白质错误折叠和聚集相关疾病药物的特点,为研发一类新的有效药物奠定了基础。

Peptide-based Strategies for Treatment of Protein Misfolding Diseases

Misfolding of native soluble proteins and peptides into insoluble amyloid aggregates is associated with a number of neurodegenerative disorders,including the most prevalent Alzheimer’s disease and Parkinson’s disease,which generally lead to cognitive decline and motor deficits.Although multiple therapies have made it to clinical trials,to date there are still no clinically effective treatments to cure these diseases or halt their progression.Development of inhibitors that prevent amyloid aggregation and recognize the toxic species to promote their clearance is one of the most important therapeutic strategies.Among different types of inhibitors,peptide-based molecules are promising candidates due to their high specificity,low toxicity,high chemical diversity,proteolytic stability and blood-brain barrier permeability after modification.Here we review the progress in research of peptide-based inhibitors towards the amyloid aggregation of Alzheimer’s disease related Aβand Tau and Parkinson’s disease relatedα-synuclein.The peptide inhibitors summarized here have been mainly generated through rational design based on the amyloidogenic sequences and fibril core structures or through random selection from peptide libraries.These peptide molecules,both naturally occurring and synthetic,can inhibit protein aggregation,disassemble amyloid fibrils,reduce cytotoxicity and some have been shown to reduce brain damage and relieve cognitive and motor impairments in animal models.These studies demonstrate the advantages of peptide-inhibitors as anti-amyloid drugs and will facilitate the discovery of new therapeutic agents.