Stapled, Long-Acting Xenopus GLP-1-Based Dual GLP-1/Glucagon Receptor Agonists with Potent Therapeutic Efficacy for Metabolic Disease

Jul 9, 2021Molecular pharmaceutics

Long-Lasting Modified Frog GLP-1 Compounds That Activate Both GLP-1 and Glucagon Receptors to Treat Metabolic Disease

AI simplified

GLP-1 Therapies on OpenScience ↗PubMed ↗DOI ↗

Abstract

A novel dual agonist, stapled xGLP/GCG-13, demonstrates potent and long-lasting effects on glucose control in rodent models.

The dual GLP-1R/GCGR agonist shows increased agonist potency and stability compared to its predecessor.
Chronic administration in diet-induced obesity models leads to significant body weight loss and improved glucose tolerance.
Enhanced energy expenditure and normalized lipid metabolism are observed in treated animals.
The approach of incorporating a serum protein-binding motif may improve the stability and effectiveness of therapeutic peptides.

AI simplified

Novel peptidic glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have increased efficacy over GLP-1R monoagonists for the treatment of diabetes and obesity. We identified a novelGLP-1-based dual GLP-1R/GCGR agonist (xGLP/GCG-13) designed with a proper activity ratio favoring the GLP-1R versus the GCGR. However, the clinical utility of xGLP/GCG-13 is limited by its shorthalf-life. Starting from xGLP/GCG-13, dual Cys mutation was performed, followed by covalent side-chain stapling and serum albumin binder incorporation, resulting in a stabilized secondary structure, enhanced agonist potency at GLP-1R and GCGR, and improved stability. The lead peptide(stapled xGLP/GCG-13 analogue with a palmitic acid albumin binder) exhibits balanced GLP-1R and GCGR activations and potent, long-lasting effects onglucose control.was further explored pharmacologically in diet-induced obesity androdent models. Chronic administration ofpotently induced body weight loss and hypoglycemic effects, improved glucose tolerance, increased energy expenditure, and normalized lipid metabolism and adiposity in relevant animal models. These results indicated thathas potential for development as a novel antidiabetic and/or antiobesity drug. Furthermore, we propose that the incorporation of a proper serum protein-binding motif into a di-Cys staple is an effective method for improving the stabilities and bioactivities of peptides. This approach is likely applicable to other therapeutic peptides, such as glucose-dependent insulin-tropic peptide receptor (GIPR) and GLP-1R dual agonists or GLP-1R/GCGR/GIPR triagonists. Xenopus in vivo in vivo db/db2c2c2c2c

Full Text

Full text is available at the source.

View full text ↗

Stapled, Long-Acting Xenopus GLP-1-Based Dual GLP-1/Glucagon Receptor Agonists with Potent Therapeutic Efficacy for Metabolic Disease

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the glp-1 therapies brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the glp-1 therapies brief