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Amyloid Peptide Scaffolds Coordinate with Alzheimer's Disease Drugs.
The Journal of Physical Chemistry B ( IF 3.3 ) Pub Date : 2019-12-27 , DOI: 10.1021/acs.jpcb.9b10368
Sai Vamshi R Jonnalagadda 1 , Andrew James Gerace 2 , Kathleen Thai 3 , Jonathan Johnson 3 , Kostas Tsimenidis 4 , Joseph M Jakubowski 1 , Christina Shen 4 , Kendal J Henderson 1 , Phanourios Tamamis 1 , Manos Gkikas 4
Affiliation  

Functional amyloid materials can combine the self-assembly of peptide scaffolds into amyloid fibrils with binding capacities for ions or compounds of pharmaceutical interest, endowed by mutable non-β-sheet-forming residues at the termini. Herein, we report the first to our knowledge amyloid materials, encompassing a GAIIG amyloidogenic core, which bind to Alzheimer's disease (AD) drugs, by mimicking the mechanism by which the same AD drugs bind to enzymes according to experimentally resolved structures, including the target enzyme acetylcholinesterase (AChE). The computationally designed amyloid scaffolds are experimentally shown to coordinate with AD drugs, using two techniques, both in dilute solutions and at higher peptide concentrations, with a higher binding capacity for donepezil and tacrine compared to that for memantine and galantamine. The binding for some of the AD drugs is strong and stable even after extensive subsequent aqueous washings, denoting high capturing efficiency by the designed biomaterials, even after incubation under physiological conditions. Our findings constitute starting points to design novel drug delivery carriers binding to one or combinations of AD drugs (e.g., NMDA and cholinesterase inhibitors).

中文翻译:

淀粉样蛋白肽支架与阿尔茨海默氏病药物协调。

功能性淀粉样物质可以将肽支架的自组装结合到淀粉样原纤维中,该淀粉样原纤维具有对离子或药学上感兴趣的化合物的结合能力,在末端具有可变的非β-折叠形成残基。在此,我们首先报道了我们知道的淀粉样物质材料,其中包括通过模拟根据实验解析的结构(包括靶标)结构相同的AD药物与酶结合的机制,结合了与阿尔茨海默氏病(AD)药物结合的GAIIG淀粉样蛋白形成核心。乙酰胆碱酯酶(AChE)。实验表明,通过计算设计的淀粉样蛋白支架可以在稀释溶液中和在较高肽浓度下使用两种技术与AD药物协同作用,与美金刚和加兰他敏相比,其对多奈哌齐和他克林的结合能力更高。即使在随后的大量水洗后,某些AD药物的结合也是牢固而稳定的,这表明设计的生物材料即使在生理条件下孵育后仍具有很高的捕获效率。我们的发现构成设计结合一种或多种AD药物(例如NMDA和胆碱酯酶抑制剂)的新型药物递送载体的起点。
更新日期:2020-01-10
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