Österlund Nicklas, Wärmländer Sebastian K T S, Gräslund Astrid
Department of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, 10691 Stockholm, Sweden.
Department of Archaeology and Classical Studies, Stockholm University, 10691 Stockholm, Sweden.
Pharmaceutics. 2022 Apr 9;14(4):823. doi: 10.3390/pharmaceutics14040823.
Cell-penetrating peptides (CPPs) with sequences derived originally from a prion protein (PrP) have been shown to exhibit both anti-prion and anti-amyloid properties particularly against prion proteins and the amyloid-β (Aβ) peptide active in Alzheimer's disease. These disease-modifying properties are so far observed in cell cultures and in vitro. The CPP sequences are composed of a hydrophobic signal sequence followed by a highly positively charged hexapeptide segment. The original signal sequence of the prion protein can be changed to the signal sequence of the NCAM1 protein without losing the anti-prion activity. Although the detailed molecular mechanisms of these CPP peptides are not fully understood, they do form amyloid aggregates by themselves, and molecular interactions between the CPPs and PrP/Aβ can be observed in vitro using various spectroscopic techniques. These initial intermolecular interactions appear to re-direct the aggregation pathways for prion/amyloid formation to less cell-toxic molecular structures (i.e., co-aggregates), which likely is why the disease-inducing PrP/Aβ aggregation is counteracted in vivo.
最初源自朊病毒蛋白（PrP）的细胞穿透肽（CPP）已被证明具有抗朊病毒和抗淀粉样蛋白特性，特别是针对在阿尔茨海默病中具有活性的朊病毒蛋白和淀粉样β（Aβ）肽。迄今为止，这些疾病修饰特性仅在细胞培养和体外实验中观察到。CPP序列由一个疏水信号序列和一个高度带正电荷的六肽段组成。朊病毒蛋白的原始信号序列可以替换为NCAM1蛋白的信号序列，而不会丧失抗朊病毒活性。尽管这些CPP肽的详细分子机制尚未完全阐明，但它们自身确实会形成淀粉样聚集体，并且使用各种光谱技术可在体外观察到CPP与PrP/Aβ之间的分子相互作用。这些最初的分子间相互作用似乎会将朊病毒/淀粉样蛋白形成的聚集途径重新导向细胞毒性较小的分子结构（即共聚集体），这可能就是体内疾病诱导性PrP/Aβ聚集受到抑制的原因。
