An improved installation of 2-hydroxy-4-methoxybenzyl(iHmb)method for chemical protein synthesis

作     者：Ying Li Long-Jie Wang Yong-Kang Zhou Jun Liang Bin Xiao Ji-Shen Zheng Ying Li;Long-Jie Wang;Yong-Kang Zhou;Jun Liang;Bin Xiao;Ji-Shen Zheng

作者机构：The First Affiliated Hospital of USTCMOE Key Laboratory for Membraneless Organelles and Cellular DynamicsDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of ChemistryUniversity of Science and Technology of ChinaHefei 230027China 

出 版 物：《Chinese Chemical Letters》 (中国化学快报（英文版）)

年 卷 期：2024年第35卷第5期

页      面：145-150页

核心收录：

学科分类：081703[工学-生物化工] 08[工学] 0817[工学-化学工程与技术] 0703[理学-化学] 0836[工学-生物工程] 

基　　金：supported by the National Key Research and Development Program of China(No.2019YFA0706900) the National Natural Science Foundation of China(Nos.22022703 and 22177108) the Collaborative Innovation Program of Hefei Science Center,CAS(No.2022HSC-CIP013) 

主　　题：Chemical protein synthesis Solid-phase peptide synthesis Removable backbone modification 2-Hydroxy-4-methoxybenzyl(Hmb)group Aspartimide-prone peptides Difficult peptides Membrane proteins 

摘      要：The 2-hydroxy-4-methoxybenzyl(Hmb)backbone modification can prevent amide bond-mediated sidereactions(e.g.,aspartimide formation,peptide aggregation)by installing the removable Hmb group into a peptide bond,thus improving the synthesis of long and challenging peptides and ***,its use is largely precluded by the limited Hmb’s installation *** this report,an improved installation of Hmb(iHmb)method was developed to achieve the flexible installation and the convenient removal of *** iHmb method involves two critical steps:(1)oxidative diazotization of the readily installed 2-hydroxy-4-methoxy-5-amino-benzyl(Hmab)to give 2-hydroxy-4-methoxy-5-diazonium-benzyl(Hmdab)by combining soamyl nitrite(IAN)/HBF_(4),and(2)reductive elimination of Hmdab to give the desired Hmb by 1,2-ethanedithiol(EDT).The iHmb method enables the installation of Hmb at any primary amino acid including the highly sterically hindered amino acids(e.g.,valine and isoleucine).The practicality and utility of the iHmb method was demonstrated by one-shot solid-phase synthesis of a challenging aspartimide-prone peptide,the mirror-image version of a hydrophobic peptide and a long-chain peptide up to ***,the iHmb method can be utilized to facilitate chemical protein ligation,as exemplified by the synthesis of the single-spanning membrane protein *** iHmb method expands the toolkit for peptide synthesis and ligation and facilitates the preparation of peptides/proteins.