Long-acting agonists of human and rodent GLP-2 receptors for studies of the physiology and pharmacological potential of the GLP-2 system.
Biomed Pharmacother
; 160: 114383, 2023 Apr.
Article
en En
| MEDLINE
| ID: mdl-36780786
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. EXPERIMENTALAPPROACH:
Six GLP-2 analogs were studied in vitro for cAMP accumulation, ß-arrestin 1 and 2 recruitment, affinity, and internalization. The trophic actions on intestine and bone were examined in vivo in rodents. KEYRESULTS:
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Roedores
/
Péptido 2 Similar al Glucagón
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Biomed Pharmacother
Año:
2023
Tipo del documento:
Article
País de afiliación:
Dinamarca