Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.
Structural and Mechanistic Insights into Development of Chemical Tools to Control Individual and Inter-Related Pathological Features in Alzheimer's Disease.
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对开发化学工具以控制阿尔茨海默氏病个体和相互相关的病理特征的结构和机制见解。
DOI：
10.1002/chem.201605401
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Lim,MiHee
中科院分区：
文献类型：
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作者：
Lee,HyuckJin;Korshavn,KyleJ;Nam,Younwoo;Kang,Juhye;Paul,ThomasJ;Kerr,RichardA;Youn,IlSeung;Ozbil,Mehmet;Kim,KwangS;Ruotolo,BrandonT;Prabhakar,Rajeev;Ramamoorthy,Ayyalusamy;Lim,MiHee
为了阐明单个和相互关联的病理因素[即淀粉样蛋白(Aβ，Aβ)、金属和氧化应激]在阿尔茨海默病(AD)发病机制中的作用，人们开发了化学工具。然而，这种工具建造所需的特性还没有明确确定；因此，现有工具或新设计的优化受到了限制。在这里，报告了在AD中发现的具有多种致病特征的关键结构属性和机制，这些属性和机制可以确定工具的调节反应性。通过合理的结构选择和变异构建了一系列的小分子，形成了一种对体外和体内金属有用的工具-β研究。变异包括：(I)A 相互作用部分的β位置和数目；(Ii) 金属结合部位；和(Iii) 密度和结构柔性。详细的生化、生物物理和计算研究能够为如何起源分子公式设计能够通过不同机制控制各种病理成分的反应的化学工具提供基础。总体而言，这项多学科研究说明了一种基于结构-机制的工具发明策略，适用于如此复杂的脑部疾病。
To elucidate the involvement of individual and inter‐related pathological factors [i.e., amyloid‐β (Aβ), metals, and oxidative stress] in the pathogenesis of Alzheimer's disease (AD), chemical tools have been developed. Characteristics required for such tool construction, however, have not been clearly identified; thus, the optimization of available tools or new design has been limited. Here, key structural properties and mechanisms that can determine tools’ regulatory reactivities with multiple pathogenic features found in AD are reported. A series of small molecules was built up through rational structural selection and variations onto the framework of a tool useful for in vitro and in vivo metal–Aβ investigation. Variations include: (i) location and number of an Aβ interacting moiety; (ii) metal binding site; and (iii) denticity and structural flexibility. Detailed biochemical, biophysical, and computational studies were able to provide a foundation of how to originate molecular formulas to devise chemical tools capable of controlling the reactivities of various pathological components through distinct mechanisms. Overall, this multidisciplinary investigation illustrates a structure–mechanism‐based strategy of tool invention for such a complicated brain disease.