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

Nov 25, 2022Chinese journal of natural medicines

Stable frog-based sugar-modified peptides that activate both blood sugar and fat metabolism receptors for treating diabetes and obesity

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Abstract

Chronic administration of the glycopeptide 1f resulted in significant body weight loss and improved glucose metabolism in mouse models.

O-GlcNAcylation enhanced the stability of the dual agonist xGLP/GCG-13 in the body.
The analog 1f showed similar receptor activation potency as xGLP/GCG-13 in cell-based assays.
In db/db and diet-induced obesity mouse models, 1f led to reduced body weight and improved glucose tolerance.
The findings indicate that glycosylation may be an effective strategy for enhancing the in vivo stability of GLP-1-based peptides.

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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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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

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