Long-acting agonists of human and rodent GLP-2 receptors for studies of the physiology and pharmacological potential of the GLP-2 system - 26/02/23

Abstract |
Background and Purpose |
Glucagon-like peptide-2 (GLP-2) is secreted postprandially from enteroendocrine Lcells and has anabolic action on gut and bone. Short-acting teduglutide is the only approved GLP-2 analog for the treatment of short-bowel syndrome (SBS). To improve the therapeutic effect, we created a series of lipidated GLP-2R agonists.
Experimental Approach |
Six GLP-2 analogs were studied in vitro for cAMP accumulation, β-arrestin 1 and 2 recruitment, affinity, and internalization. The trophic actions on intestine and bone were examined in vivo in rodents.
Key Results |
Lipidations at lysines introduced at position 12, 16, and 20 of hGLP-2(1−33) were well-tolerated with less than 2.2-fold impaired potency and full efficacy at the hGLP-2R in cAMP accumulation. In contrast, N- and C-terminal (His1 and Lys30) lipidations impaired potency by 4.2- and 45-fold and lowered efficacy to 77% and 85% of hGLP-2, respectively. All variants were similarly active on the rat and mouse GLP-2Rs and the three most active variants displayed increased selectivity for hGLP-2R over hGLP-1R activation, compared to native hGLP-2. Impact on arrestin recruitment and receptor internalization followed that of Gαs-coupling, except for lipidation in position 20, where internalization was more impaired, suggesting desensitization protection. A highly active variant (C16 at position 20) with low internalization and a half-life of 9.5 h in rats showed improved gut and bone tropism with increased weight of small intestine in mice and decreased CTX levels in rats.
Conclusion and implication |
We present novel hGLP-2 agonists suitable for in vivo studies of the GLP-2 system to uncover its pharmacological potential.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Lipidation of GLP-2 is best carried out in the middle part of the peptide backbone. |
• | Lipidation of GLP-2 prolongs the half-life beyond that obtained from other approaches. |
• | Long-acting GLP-2 analog with high activity across the human, rat and mouse GLP-2R. |
• | Lipidation of GLP-2 at position 20 protects against receptor desensitization. |
• | Improved gut and bone tropic actions in rodents administrated with long-acting GLP-2. |
Abbreviation : BMD, CTX, DPP-4, GCGR, GIP, GIPR, GLP-1, GLP-1R, GLP-2, GLP-2R, HSA, OVX, RIA, SBS
Keywords : Glucagon-like peptide-2 (GLP-2), GLP-2 receptor (GLP-2R), Protein lipidation, Receptor agonist, Bone metabolism, Intestinal growth
Plan
Vol 160
Article 114383- avril 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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