TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides.
TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides.
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受 TANGO 启发的抗淀粉样环肽设计。
DOI：
10.1021/acschemneuro.6b00150
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发表时间：
2016
影响因子：
5
通讯作者：
Murphy,ReginaM
中科院分区：
文献类型：
--
作者：
Lu,Xiaomeng;Brickson,ClaireR;Murphy,ReginaM
β-淀粉样肽（a β）自结合成低聚物和原纤维，这一过程被认为直接导致阿尔茨海默病中的神经元死亡。与Aβ结合并抑制纤维形成和神经毒性的化合物是一种抗阿尔茨海默病治疗策略。肽在这方面特别有吸引力，因为它们在破坏蛋白质-蛋白质相互作用方面比小分子有优势，但与抗体不同，它们可以通过化学手段调整其性质。自互补和肽库筛选是寻找与Aβ结合的肽的两种策略。我们采用了不同的方法，利用转甲状腺素（TTR）作为模板设计a β结合肽。之前，我们证明了一种环肽，其序列来源于已知的TTR上的a β结合位点，可以抑制a β聚集到原纤维中，并保护神经元免受a β毒性。在这里，我们通过使用TANGO算法（最初设计用于识别蛋白质中的淀粉样蛋白序列）来搜索具有更高功效的环肽。利用TANGO预测序列修饰对构象和聚集的影响，我们合成了一个明显改进的环状肽。我们证明，与Aβ结合的肽将Aβ重定向到蛋白酶敏感的非纤维聚集体。利用这种方法设计的环肽具有良好的溶解度、特异性和稳定性。
β-Amyloid peptide (Aβ) self-associates into oligomers and fibrils, in a process that is believed to directly lead to neuronal death in Alzheimer’s disease. Compounds that bind to Aβ, and inhibit fibrillogenesis and neurotoxicity, are of interest as an anti-Alzheimer therapeutic strategy. Peptides are particularly attractive for this purpose, because they have advantages over small molecules in their ability to disrupt protein–protein interactions, yet they are amenable to tuning of their properties through chemical means, unlike antibodies. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to Aβ. We have taken a different approach, by designing Aβ-binding peptides using transthyretin (TTR) as a template. Previously, we demonstrated that a cyclic peptide, with sequence derived from the known Aβ-binding site on TTR, suppressed Aβ aggregation into fibrils and protected neurons against Aβ toxicity. Here, we searched for cyclic peptides with improved efficacy, by employing the algorithm TANGO, designed originally to identify amyloidogenic sequences in proteins. By using TANGO as a guide to predict the effect of sequence modifications on conformation and aggregation, we synthesized a significantly improved cyclic peptide. We demonstrate that the peptide, in binding to Aβ, redirects Aβ toward protease-sensitive, nonfibrillar aggregates. Cyclic peptides designed using this strategy have attractive solubility, specificity, and stability characteristics.