以色列理工学院Galia Maayan团队报道了一种可从淀粉样蛋白中去除Cu2+的水溶性肽螯合剂以及阻止与阿尔茨海默病相关的活性氧物种的形成。相关研究成果于2021年9月12日发表于国际顶尖学术期刊《德国应用化学》。
与淀粉样β（Aβ）肽结合的铜可作为活性氧（ROS）形成的催化剂，导致与阿尔茨海默病（AD）相关的神经病理学降解。一种好的治疗方法是使用一种螯合剂，可以选择性地从Cu-Aβ中去除Cu。该螯合剂应与突触间隙中存在的Zn2+离子（Zn）竞争，同时形成无毒的铜络合物。
该文中，研究人员报道了了P3，一种水溶性拟肽螯合剂，其在存在锌的情况下选择性地从Cu-Aβ中去除Cu（II），并且即使在还原环境中也防止ROS的形成。基于广泛的光谱分析，研究人员发现，尽管P3从Cu中提取Zn，Zn-Aβ的速度比去除Cu的速度快，但形成的Zn络合物是进一步解离的动力学产物，而CuP3是作为唯一稳定的热力学产物形成的。
研究人员首次发现，结合类肽的生物利用，使P3成为AD中一种优秀的候选药物。
附：英文原文
Title: A Water-Soluble Peptoid Chelator that Can Remove Cu2+ from Amyloid-β and Stop the Formation of Reactive Oxygen Species Associated with Alzheimer’s Disease
Author: Galia Maayan, Anastasia E. Behar, Laurent Sabater, Maria Baskin, Christelle Hureau
Issue&Volume: 2021-09-12
Abstract: Cu bound to Amyloid-β (Aβ) peptides can act as a catalyst for the formation of reactive oxygen species (ROS), leading to neuropathologic degradation associated with Alzheimer’s disease (AD). An excellent therapeutic approach is to use a chelator that can selectively remove Cu from Cu-Aβ. This chelator should compete with Zn2+ ions (Zn) that are present in the synaptic cleft while forming a nontoxic Cu complex. Herein we describe P3, a water-soluble peptidomimetic chelator that selectively removes Cu(II) from Cu-Aβ in the presence of Zn and prevent the formation of ROS even in a reductive environment. We demonstrate, based on extensive spectroscopic analysis, that although P3 extracts Zn from Cu,Zn-Aβ faster than in removes Cu, the formed Zn complexes are kinetic products that further dissociate, while CuP3 is formed as an exclusive stable thermodynamic product. Our unique findings, combined with the bioavailability of peptoids, make P3 an excellent drug candidate in the context of AD.
DOI: 10.1002/anie.202109758
Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202109758
