α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo

作     者：Yan Shi Candy Lee Peng Sang Zaid Amso David Huang Weixia Zhong Meng Gu Lulu Wei Vân T.B.Nguyen-Tran Jingyao Zhang Weijun Shen Jianfeng Cai Yan Shi;Candy Lee;Peng Sang;Zaid Amso;David Huang;Weixia Zhong;Meng Gu;Lulu Wei;Van T.B.Nguyen-Tran;Jingyao Zhang;Weijun Shen;Jianfeng Cai

作者机构：Department of ChemistryUniversity of South FloridaTampaFL 33620USA Calibr at Scripps ResearchLa JollaCA 92037USA 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第4期

页      面：1648-1659页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 100701[医学-药物化学] 10[医学] 

基　　金：supported by NIH R01AI152416(to Jianfeng Cai,USA) NIH R01 AG056569(to Jianfeng Cai,USA) 

主　　题：GLP-1 Peptidomimetics Helical structures Stability Type-2 diabetes treatments Rational design GLP-1R agonists Pharmacological activity 

摘      要：Peptides are increasingly important resources for biological and therapeutic development,however,their intrinsic susceptibility to proteolytic degradation represents a big *** a natural agonist for GLP-1R,glucagon-like peptide 1(GLP-1)is of significant clinical interest for the treatment of type-2 diabetes mellitus,but its in vivo instability and short half-life have largely prevented its therapeutic ***,we describe the rational design of a series of a/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R *** GLP-1 hybrid analogues exhibited enhanced stability(t_(1/2)14 days)compared to t_(1/2)(1 day)of GLP-1 in the blood plasma and in *** newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes ***,our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.