Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors

Jul 20, 2020Biochemical pharmacology

Testing how drugs that activate both GLP-1 and glucagon receptors may favor certain cell responses

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Abstract

All novel peptides demonstrated distinct biased agonism profiles relative to their receptor counterparts.

Selective GLP-1 receptor agonists are important therapeutics for type 2 diabetes and obesity.
Polypharmacological approaches aim to target multiple metabolic receptors with a single drug.
Agonists targeting both GLP-1R and glucagon receptor (GCGR) may exhibit biased signaling.
Three dual agonists showed varying potency in activating cAMP production between GLP-1R and GCGR.
The pharmacological profiles of these peptides highlight the need for careful consideration of selectivity and bioavailability in drug development.

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Metabolic diseases such as obesity, diabetes, and their comorbidities have converged as one of the most serious health concerns on a global scale. Selective glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists are one of the major therapeutics for type 2 diabetes and obesity. Polypharmacological approaches that enable modulation of multiple metabolic targets in a single drug have emerged as a potential avenue to improve therapeutic outcomes. Among numerous peptides under development are those targeting the GLP-1R and either the glucagon receptor (GCGR), glucose-dependent insulinotropic peptide receptor (GIPR) or all 3 receptors, as dual- or tri- peptide agonists. Despite many of them entering into clinical trials, current development has been based on only a limited understanding of the spectrum of potential pharmacological properties of these ligands beyond binding selectivity. In the present study, we examined the potential for agonists that target both GLP-1R and GCGR to exhibit biased agonism, comparing activity across proximal activation of Gs protein, cAMP accumulation, pERK1/2 and β-arrestin recruitment. Three distinct dual agonists that have different relative cAMP production potency for GLP-1R versus GCGR, "peptide 15", MEDI0382 and SAR425899, and one triagonist of the GLP-1R, GCGR and GIPR were examined. We demonstrated that all novel peptides have distinct biased agonism profiles relative to either of the cognate agonists of the receptors, and to each other. This is an important feature of the pharmacology of this drug class that needs to be considered alongside selectivity, bioavailability and pharmacokinetics for rational optimization of new therapeutics.

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Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors

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