"Click peptide" based on the "O-acyl isopeptide method":: Control of Aβ1-42 production from a photo-triggered Aβ1-42 analogue
"Click peptide" based on the "O-acyl isopeptide method":: Control of Aβ1-42 production from a photo-triggered Aβ1-42 analogue
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DOI：
10.1021/ja057100v
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发表时间：
2006-01-25
影响因子：
15
通讯作者：
Kiso, Y
中科院分区：
文献类型：
--
作者：
Taniguchi, A;Sohma, Y;Kiso, Y
清楚地了解淀粉样β肽（Aβ）1 - 42的动态事件，例如折叠、自组装和聚集过程，对于阿尔茨海默病（AD）研究具有重要意义。然而，由于不受控制的聚合，这些Aβ1−42动态事件的阐明是一个困难的问题，这也为建立阐明Aβ1−42病理功能的实验系统带来了重大障碍。在O-酰基异肽法的基础上，我们开发了一种新的Aβ1−42的光触发“点击肽”，例如26-N-NATRA-26-AIAβ42，其中在26-O-酰基异A β1−42（26-AIAβ42）的Ser 26的α-氨基上引入了可光裂解的6-硝基乙酰氧基羰基（NATRA）。从结果来看，（1）由于一个单一的修饰酯，点击肽在生理条件下没有表现出自组装性质;（2）点击肽的光照射和随后的O-N分子内酰基迁移通过快速和单向的转化反应（所谓的“点击”）提供了完整的Aβ1 - 42，而点击肽在非光解或储存条件下是稳定的。此外，在转化为Aβ1−42的过程中没有释放额外的原纤维抑制助剂是有利的。该方法提供了一种新的系统，可用于通过诱导激活Aβ 1 - 42自组装来研究AD中Aβ1 - 42的动态生物学功能。
A clear understanding of the dynamic events of amyloid β peptide (Aβ) 1−42, such as the folding, self-assembly, and aggregation processes, would be of great significance in Alzheimer's disease (AD) research. However, elucidation of these Aβ1−42 dynamic events is a difficult issue due to uncontrolled polymerization, which also poses a significant obstacle for establishing an experimental system that clarifies the pathological function of Aβ1−42. On the basis of theO-acyl isopeptide method, we herein developed a novel photo-triggered “click peptide” of Aβ1−42, for example, 26-N-Nvoc-26-AIAβ42, in which the photocleavable 6-nitroveratryloxycarbonyl (Nvoc) group was introduced at the α-amino group of Ser26in 26-O-acyl isoAβ1−42 (26-AIAβ42). From the results, (1) the click peptide did not exhibit the self-assembling nature under physiological conditions due to one single modified ester; (2) photoirradiation of the click peptide and subsequent O−N intramolecular acyl migration afforded the intact Aβ1−42 with a quick and one-way conversion reaction (so-called “click”), while the click peptide was stable under nonphotolytic or storage conditions. In addition, it is advantageous that no additional fibril inhibitory auxiliaries were released during conversion to Aβ1−42. This method provides a novel system useful for investigating the dynamic biological functions of Aβ1−42 in AD by inducible activation of Aβ1−42 self-assembly.