Macrocyclization and Labeling of Helix-Loop-Helix Peptide With Intramolecular bis-Thioether Linkage
Macrocyclization and Labeling of Helix-Loop-Helix Peptide With Intramolecular bis-Thioether Linkage
复制标题
DOI：
10.1002/bip.22826
复制
发表时间：
2016-07-01
期刊：
影响因子：
2.9
通讯作者：
Fujii, Ikuo
中科院分区：
文献类型：
--
作者：
Nishihara, Toshio;Kitada, Hidekazu;Fujii, Ikuo
Conformationally constrained peptides have been developed as an inhibitor for protein-protein interactions (PPIs), and we have de novo designed cyclized helix-loop-helix (cHLH) peptide with a disulfide bond consisting of 40 amino acids to generate molecular-targeting peptides. However, synthesis of long peptides has sometimes resulted in low yield according to the respective amino acid sequences. Here we developed a method for efficient synthesis and labeling for cHLH peptides. First, we synthesized two peptide fragments and connected them by the copper-mediated alkyne and azide cycloaddition (CuAAC) reaction. Cyclization was performed by bis-thioether linkage using 1,3-dibromomethyl-5-propargyloxybenzene, and subsequently, the cHLH peptide was labeled with an azide-labeled probe. Finally, we designed and synthesized a peptide inhibitor for the p53-HDM2 interaction using a structure-guided design and successfully labeled it with a fluorescent probe or a functional peptide, respectively, by click chemistry. This macrocyclization and labeling method for cHLH peptide would facilitate the discovery of de novo bioactive ligands and therapeutic leads. (C) 2016 Wiley Periodicals, Inc.
