Design of Novel Exendin-Based Dual Glucagon-like Peptide 1 (GLP-1)/Glucagon Receptor Agonists

Abstract

Dual activation of the glucagon-like peptide 1 (GLP-1) and glucagon receptor has the potential to lead to a novel therapy principle for the treatment of diabesity. Here, we report a series of novel peptides with dual activity on these receptors that were discovered by rational design. On the basis of sequence analysis and structure-based design, structural elements of glucagon were engineered into the selective GLP-1 receptor agonist exendin-4, resulting in hybrid peptides with potent dual GLP-1/glucagon receptor activity. Detailed structure-activity relationship data are shown. Further modifications with unnatural and modified amino acids resulted in novel metabolically stable peptides that demonstrated a significant dose-dependent decrease in blood glucose in chronic studies in diabetic db/db mice and reduced body weight in diet-induced obese (DIO) mice. Structural analysis by NMR spectroscopy confirmed that the peptides maintain an exendin-4-like structure with its characteristic tryptophan-cage fold motif that is responsible for favorable chemical and physical stability.

Running on mixed fuel‐dual agonistic approach of GLP‐1 and GCG receptors leads to beneficial impact on body weight and blood glucose control: A comparative study between mice and non‐human primates

“…As a result of these design activities, the “mouse dual agonist” was obtained. Subcutaneous administration of this peptide (1 mg/kg) in healthy mice showed a half‐life of 3.2 hours, similar to that of liraglutide (3.6 hours) but with a lower exposure …”

“…We recently reported that dual GLP‐1R/GCGR agonists, which are structurally based on the exendin‐4 sequence, benefit from the favourable physicochemical properties of exendin‐4 . These new dual agonists carry a fatty acid side chain on position 14 to improve half‐life.…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…Following their introduction in 2009 (Day et al, 2009), several dual agonists targeting the receptors for GLP-1 and glucagon have been developed (Fig. 3) and their efficacy translates from obese rodents to nonhuman primates and humans (Day et al, 2009;Pocai et al, 2009;Henderson et al, 2016;Tschop et al, 2016;Evers et al, 2017).…”

Twincretin as a potential therapeutic for the management of type 2 diabetes with obesity

“…Recently, several GLP‐1/GR dual agonists have been under development (Table ). Preclinical studies showed that the GLP‐1R/GR dual agonist, SAR425899 (Sanofi, Paris, France), decreased bodyweight in diet‐induced obese mice and ameliorated glucose levels in db / db mice, and that the GLP‐1R/GR dual agonist, MEDI0382 (MedImmune, Gaithersburg, MD, USA), significantly reduced bodyweight and improved glucose tolerance to levels similar to those obtained by the GLP‐1R agonist, liraglutide, in non‐human primates. Based on the promising results with GLP‐1R/GIPR and GLP‐1R/GR dual agonists, GLP‐1R/GIPR/GR triple agonists also have been under development as therapeutics for type 2 diabetes (Table ).…”