Mapping the binding site topology of amyloid protein aggregates using multivalent ligands.
Mapping the binding site topology of amyloid protein aggregates using multivalent ligands.
复制标题
使用多价配体绘制淀粉样蛋白聚集体的结合位点拓扑。
DOI：
10.1039/d1sc01263k
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发表时间：
2021-07-01
期刊：
影响因子：
8.4
通讯作者：
Hunter CA
中科院分区：
文献类型：
--
作者：
Sanna E;Rodrigues M;Fagan SG;Chisholm TS;Kulenkampff K;Klenerman D;Spillantini MG;Aigbirhio FI;Hunter CA
神经退行性疾病如阿尔茨海默病和帕金森病的发展中的关键过程是蛋白质聚集以产生具有交叉β-折叠结构（淀粉样蛋白）的非淀粉性聚集体。开发能够以高亲和力和选择性结合这些聚集体的试剂具有早期疾病诊断的潜力。通过将两个苯并噻唑苯胺（BTA）头基与不同长度的聚乙二醇（PEG）间隔基连接，已经获得了以低纳摩尔亲和力结合淀粉样蛋白原纤维的荧光探针。测量的与Aβ、α-突触核蛋白和tau原纤维相互作用的解离常数表明，接头的长度决定了结合亲和力和选择性。这些化合物已成功用于体外和帕金森病患者死后脑组织中α-突触核蛋白聚集体的成像。结果表明，多价配体提供了一种强有力的方法，以获得高亲和力，选择性试剂结合神经退行性疾病中形成的神经元聚集体。多价配体提供了一种强有力的方法来获得高亲和力试剂，以结合在神经退行性疾病中形成的聚集体。通过使用不同的接头连接头部基团来实现对不同蛋白质的选择性。
A key process in the development of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases is the aggregation of proteins to produce fibrillary aggregates with a cross β-sheet structure, amyloid. The development of reagents that can bind these aggregates with high affinity and selectivity has potential for early disease diagnosis. By linking two benzothiazole aniline (BTA) head groups with different length polyethylene glycol (PEG) spacers, fluorescent probes that bind amyloid fibrils with low nanomolar affinity have been obtained. Dissociation constants measured for interaction with Aβ, α-synuclein and tau fibrils show that the length of the linker determines binding affinity and selectivity. These compounds were successfully used to image α-synuclein aggregates in vitro and in the post-mortem brain tissue of patients with Parkinson's disease. The results demonstrate that multivalent ligands offer a powerful approach to obtain high affinity, selective reagents to bind the fibrillary aggregates that form in neurodegenerative disease. Multivalent ligands offer a powerful approach to obtain high affinity reagents to bind the aggregates that form in neurodegenerative disease. Selectivity for different proteins was achieved by using different linkers to connect the head groups.
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