Development of O-acyl isopeptide method
Development of O-acyl isopeptide method
复制标题
DOI：
10.1002/bip.20683
复制
发表时间：
2007-01-01
期刊：
影响因子：
2.9
通讯作者：
Kiso, Yoshiaki
中科院分区：
文献类型：
--
作者：
Sohma, Youhei;Yoshiya, Taku;Kiso, Yoshiaki
在对天冬氨酸蛋白酶抑制剂和水不溶性前药进行十多年的研究期间，2003年，我们发现肽主链中O-酰基而不是N-酰基残基的存在显着改变了天然肽的二级结构。此外，随后通过O-N分子内酰基迁移反应生成目标肽。这些发现导致了一种新方法的开发，称为“O-酰基异肽法”，用于合成含有困难序列的肽。该方法进一步应用于阿尔茨海默氏症Aβ1-42，结果表明Aβ1-42的O-酰基异肽可以有效合成和储存，而无需自发自组装。然后可以在生理实验条件下从异肽获得完整的单体Aβ1-42。我们将 O-酰基异肽命名为“Click Peptide”，因为它能够“快速、轻松地单向转化”至母体 A beta 1-42。点击肽的应用为通过诱导激活Aβ1-42自组装来研究Aβ1-42的生物学功能提供了新的基础。随着我们最近开发的“O-酰基异二肽单元”和“无外消旋片段缩合方法”，O-酰基异肽方法进一步发展为肽合成的通用方法。异二肽单元避免了树脂上通常困难的酯化反应，使得 O-酰基异肽方法的常规使用成为可能。 “无外消旋链段缩合方法”是通过使用具有 C 末端氨基甲酸酯保护的 O-酰基 Ser/Thr 残基的 N 链段实现的。因此，通过无外消旋化片段缩合合成长肽/蛋白质已成为可能，在 Ser/Thr 残基而不是 C 端 Gly/Pro 残基上进行。随着O-酰基异肽方法的应用越来越广泛，我们撰写了这篇综述，以促进其在肽和蛋白质生产中的应用。 (c) 2007 年 Wiley 期刊公司。
During over a decade of study on aspartic protease inhibitors and water insoluble prodrugs, in 2003, we discovered that the presence of an O-acyl instead of N-acyl residue within the peptide backbone significantly changed the secondary structure of the native peptide. In addition, the target peptide was subsequently generated by an O-N intramolecular acyl migration reaction. These findings led to the development of a novel method, called "O-acyl isopeptide method", for the synthesis of peptides containing difficult sequence. Further application of the method to Alzheimer's A beta 1-42 revealed that the O-acyl isopeptide of A beta 1-42 could be effectively synthesized and stored without spontaneous self-assembly. Intact monomer A beta 1-42 could then be obtained from the isopeptide under physiological experimental conditions. We named the O-acyl isopeptide "Click Peptide", because of its "quick and easy one-way conversion" to the parent A beta 1-42. Application of the click peptide has provided a new basis for the investigation of the biological functions of A beta 1-42 by inducible activation of its self-assembly. The O-acyl isopeptide method has further evolved as a general method for peptide synthesis with our recent developments of "O-acyl isodipeptide units" and "racemization-free segment condensation methodology". Isodipeptide units have enabled routine use of the O-acyl isopeptide method by avoiding the often difficult esterification reaction on resin. "Racemization-free segment condensation methodology" has been achieved by employing N-segments possessing a C-terminal urethane-protected O-acyl Ser/Thr residues. The synthesis of long peptides/proteins by racemization-free segment condensation has thus become possible at Ser/Thr residues instead of C-terminal Gly/Pro residues. As the O-acyl isopeptide method becomes more widely utilized, we have composed this review to facilitate its application for the production of peptides and proteins. (c) 2007 Wiley Periodicals, Inc.