4.6 Article

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

期刊

CHINESE JOURNAL OF NATURAL MEDICINES
卷 20, 期 11, 页码 863-872

出版社

CHINESE JOURNAL NATURAL MEDICINES
DOI: 10.1016/S1875-5364(22)60196-1

关键词

Glucagon-like peptide-1; Glucagon; Diabetes; Obesity; O-GlcNAcylation

资金

  1. Fundamental Research Funds for the Central Universities [JUSRP51712B]
  2. Natural Science Foundation of Xuzhou [KC19154]
  3. Open Project Program of Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Guangxi Medical University [GKE-KF202006]

向作者/读者索取更多资源

Peptide dual agonists that target both GLP-1R and GCGR receptors have emerged as potential therapeutics for treating type 2 diabetes with obesity. O-GlcNAcylation was shown to improve the stability of a dual GLP-1R/GCGR agonist, leading to significant weight loss and hypoglycemic effects.
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.

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