Exploiting Complex-Type N-Glycan to Improve the in Vivo Stability of Bioactive Peptides  

作　　者：Qijia Wei Jun Zhang Yuankun Dao Mengliang Ye Dangliang Liu Weidong Dong Ning Yuan Hongxing Li Chunli Song Mo Li Xiaomeng Shi Suwei Dong 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs,Peking University,Beijing 100191 [2]Chemical Biology Center,Peking University,Beijing 100191 [3]Department of Chemical Biology,School of Pharmaceutical Sciences,Peking University,Beijing 100191 [4]Department of Orthopedics,Peking University Third Hospital,Beijing 100191 [5]Center for Reproductive Medicine,Department of Obstetrics and Gynecology,Peking University Third Hospital,Beijing 100191 [6]National Clinical Research Center for Obstetrics and Gynecology,Peking University Third Hospital,Beijing 100191 [7]Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology,Peking University Third Hospital,Beijing 100191

出　　处：《CCS Chemistry》2023年第7期1623-1634,共12页中国化学会会刊（英文）

基　　金：This research was made possible as a result of a generous grant from the Beijing National Science Foundation(grant no.JQ18024);the National Key R&D Program of China(grant no.2018YFA0507602);the National Natural Science Foundation of China(grant nos.91953111 and 91853113).

摘　　要：Peptides can be potentmolecules with high efficacy and selectivity in the development of biotherapeutics.However,the poor pharmacokinetic properties of peptides pose major challenges for their broader medicinal applications.Inspired by the proteinstabilizing role of natural N-glycosylation,we design and synthesize a series of parathyroid hormone(PTH)peptides(1-34),bearing either N-GlcNAc or biantennary complex-type N-glycan modification,and evaluate their serum stability and biological activities.The results indicate that an N-Asn-linked complex-type sialylundecasaccharide can increase the serum half-life and in vivo bioactivity of PTH peptides with a broad tolerance of modification sites.Further,hydrogen/deuterium exchange mass spectroscopy indicates that the larger-sized Nglycan can induce enhanced hydration dynamics in its surroundings,which may facilitate an improved resistance for the peptide against enzymatic proteolysis.This sialylundecasaccharide-based peptideengineering strategy has also been applied to glucagon-like peptide-1(7-37),leading to glycopeptides with enhanced hypoglycemic activity and acting time in vivo.Together,these results demonstrate the potential of using sialylated complextype N-glycan as a general engineering strategy for developing long-acting peptide therapeutics.

关 键 词：therapeutic peptides STABILITY Nglycosylation solid-phase peptide synthesis chemoenzymatic approach hydrogen-deuterium exchange mass spectrometry 

分 类 号：O62[理学—有机化学]