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 prev...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 identified 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 improved the stability of xGLP/GCG-13 in vivo.Importantly,chronic administration of 1f potently induced body weight loss and hypoglycemic 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.展开更多
基金supported by the Fundamental Research Funds for the Central Universities(No.JUSRP51712B)the Natural Science Foundation of Xuzhou(No.KC19154)the Open Project Program of Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor,Ministry of Education,Guangxi Medical University(No.GKE-KF202006)。
文摘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 identified 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 improved the stability of xGLP/GCG-13 in vivo.Importantly,chronic administration of 1f potently induced body weight loss and hypoglycemic 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.
