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 

机构地区：[1]Department of Chemistry,University of South Florida,Tampa,FL 33620,USA [2]Calibr at Scripps Research,La Jolla,CA 92037,USA

出　　处：《Acta Pharmaceutica Sinica B》2023年第4期1648-1659,共12页药学学报（英文版）

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

摘　　要：Peptides are increasingly important resources for biological and therapeutic development,however,their intrinsic susceptibility to proteolytic degradation represents a big hurdle.As 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 application.Here,we describe the rational design of a series of a/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists.Certain 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 vivo.These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment.Additionally,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.

关 键 词：GLP-1 PEPTIDOMIMETICS Helical structures Stability Type-2 diabetes treatments Rational design GLP-1R agonists Pharmacological activity 

分 类 号：R914[医药卫生—药物化学]