The effects of Fc fusion protein glucagon-like peptide-1 and glucagon dual receptor agonist with different receptor selectivity in vivo studies - 27/04/24
Abstract |
Background |
Glucagon-like peptide-1 (GLP-1)/glucagon (GCG) dual receptor agonists with different receptor selectivity are under investigation and have shown significant improvement in both weight loss and glycemic control, but the optimal potency ratio between the two receptors to balance efficacy and safety remains unclear.
Experimental approach |
We designed and constructed several dual receptor agonists with different receptor potency ratios using Fc fusion protein technology. The long-term effects of the candidates on body weight and metabolic dysfunction-associated steatotic liver disease (MASLD) were evaluated in diet-induced obese (DIO) model mice, high-fat diet (HFD)-ob/ob mice and AMLN diet-induced MASLD mice. Repeat dose toxicity assays were performed to investigate the safety profile of the candidate (HEC-C070) in Sprague Dawley (SD) rats.
Key results |
The high GCG receptor (GCGR) selectivity of HEC-C046 makes it more prominent than other compounds for weight loss and most MASLD parameters but may lead to safety concerns. The weight change of HEC-C052 with the lowest GCG agonism was inferior to that of selective GLP-1 receptor agonist (GLP-1RA) semaglutide in DIO model mice. The GLP-1R selectivity of HEC-C070 with moderate GCG agonism has a significant effect on weight loss and liver function in obese mice, and its lowest observed adverse effect level (LOAEL) was 30 nmol/kg in the repeat dose toxicity study.
Conclusion |
We compared the potential of the Fc fusion protein GLP-1/GCG dual receptor agonists with different receptor selectivity to provide the setting for future GLP-1/GCG dual receptor agonists to treat obesity and MASLD.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | A series of different ratios of GLP-1R/GCGR dual agonists were designed based on the sequence of human GCG. |
• | GLP-1R/GCGR dual agonists improved body weight, fatty liver and glycaemic control in vivo. |
• | GLP-1R/GCGR dual agonists have greater potential in the treatment ofmetabolic diseases than that of GLP-1R agonists. |
• | The activity of GCG in GLP-1R/GCGR dual agonists can be enhanced as high as possible provided it is safe. |
Keywords : Glucagon, GLP-1, Obesity, MASLD, Weight loss
Plan
Vol 174
Article 116485- mai 2024 Retour au numéro
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