Peptide dual agonists toward both glucagon-like peptide 1 receptor(GLP-1R)and glucagon receptor(GCGR)are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus(T2DM)patients with obesity.Our previous work identi-fied a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13,which showed decent hypoglycemic and body weight lowering activity.However,the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life.Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins,we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/GCGR dual agonists.One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays.As expected,O-GlcNAcylation effectively im-proved the stability of xGLP/GCG-13 in vivo.Importantly,chronic administration of 1f potently induced body weight loss and hy-poglycemic effects,improved glucose tolerance,and normalized lipid metabolism and adiposity in both db/db and diet induced obesity(DIO)mice models.These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.

LI Qiang;YANG Qimeng;HAN Jing;LIU Xiaohan;FU Junjie;YIN Jian

Key Laboratory of Carbohydrate Chemistry and Biotechnology,Ministry of Education,School of Biotechnology,Jiangnan Uni-versity,Wuxi 214122,China;School of Chemistry and Materials Science,Jiangsu Normal University,Xuzhou 221116,China;Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor,Ministry of Education,Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor,Guangxi Medical University,Nanning 530021,China

中国天然药物

[1]LI Qiang;YANG Qimeng;HAN Jing;LIU Xiaohan;FU Junjie;YIN Jian-.Xenopus GLP-1-based glycopeptides as dual glucagon-like peptide 1 receptor/glucagon receptor agonists with improved in vivo stability for treating diabetes and obesity)[J].中国天然药物,2022(11):863-872

xGLP,GlcNAcylated,equipotent,poglycemic

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