Journal of medicinal chemistryApr 28, 2017

Design of New Exendin-Based Drugs Targeting Both GLP-1 and Glucagon Receptors

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 5, 2026

Abstract

Novel peptides with dual activity on GLP-1 and glucagon receptors may offer a new approach for treating diabesity.

Peptides were engineered by incorporating structural elements of glucagon into the GLP-1 receptor agonist exendin-4.
These hybrid peptides exhibited potent activity on both the GLP-1 and glucagon receptors.
Metabolically stable peptides showed a significant dose-dependent decrease in blood glucose levels in diabetic db/db mice.
In diet-induced obese (DIO) mice, the peptides also resulted in reduced body weight.
Structural analysis confirmed that the peptides retain an exendin-4-like structure, contributing to their stability.

Simplified

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.

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Design of New Exendin-Based Drugs Targeting Both GLP-1 and Glucagon Receptors

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