Chirality Dependence of Amyloid Cellular Uptake and a New Mechanistic Perspective
Chirality Dependence of Amyloid Cellular Uptake and a New Mechanistic Perspective
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DOI：
10.1002/cbic.201800708
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发表时间：
2019-04-15
期刊：
影响因子：
3.2
通讯作者：
Raskatov, Jevgenij A.
中科院分区：
文献类型：
--
作者：
Dutta, Subrata;Finn, Thomas S.;Raskatov, Jevgenij A.
淀粉样蛋白是一种可形成多种神经毒性聚集体的固有无序肽，其42个氨基酸的同种型被认为是导致阿尔茨海默病（AD）的因子。细胞对肽的摄取是它能够发挥其许多毒性作用的关键步骤。细胞摄取过程是复杂的，并且已经提出了许多竞争性内化途径。迄今为止，仍不清楚哪些摄取机制对整个过程特别重要，需要改进这种理解，以便设计更好的分子AD治疗剂。手性可以作为一个独特的工具来研究这一过程，因为一些建议的机制预计将进行立体选择性的方式，而其他人没有。为了阐明这一重要问题，我们合成了荧光标记的淀粉样蛋白对映体，并量化了它们的细胞摄取，发现摄取以立体选择性方式发生，对l立体异构体的典型偏好约为5：1。这表明，该过程主要是受体介导的，与非立体选择性机制可能较小的贡献。
Amyloid is an inherently disordered peptide that can form diverse neurotoxic aggregates, and its 42-amino-acid isoform is believed to be the agent responsible for Alzheimer's disease (AD). Cellular uptake of the peptide is a pivotal step for it to be able to exert many of its toxic actions. The cellular uptake process is complex, and numerous competing internalization pathways have been proposed. To date, it remains unclear which of the uptake mechanisms are particularly important for the overall process, and improvement of this understanding is needed, so that better molecular AD therapeutics can be designed. Chirality can be used as a unique tool to study this process, because some of the proposed mechanisms are expected to proceed in stereoselective fashion, whereas others are not. To shed light on this important issue, we synthesized fluorescently labeled enantiomers of amyloid and quantified their cellular uptake, finding that uptake occurs in stereoselective fashion, with a typical preference for the l stereoisomer of approximate to 5:1. This suggests that the process is predominantly receptor-mediated, with likely minor contributions of non-stereoselective mechanisms.