Discovery of novel glucagon-like peptide 1/cholecystokinin 1 receptor dual agonists

The combined use of gastrointestinal hormones for treating metabolic diseases is gaining increasing attention. The potential of developing novel dual agonists targeting both cholecystokinin 1 (CCK-1) receptor and glucagonlike peptide 1 (GLP-1) receptor to improve the treatment of type 2 diabetes and obesity have not been fully explored. In this investigation, we reported a series of novel GLP-1/CCK-1 receptor co-agonists constructed by linking the C -terminus of a GLP-1 receptor agonist (bullfrog GLP-1) to the N -terminus of a CCK-1 receptor selective agonist NN9056. In comprehensive in vitro assays, these co-agonists exhibited complete agonistic potency on GLP-1 and CCK-1 receptor. Remarkably, 1f displayed superior hypoglycemic and insulinotropic effects when compared to NN9056 and semaglutide. Evaluation in Kunming and diet-induced obesity (DIO) mice unveiled significant acute and enduring hypoglycemic effects of 1f . Administration of 1f to DIO mice resulted in substantial weight loss, normalized lipid metabolism, and enhanced glucose regulation. These preclinical observations strongly advocate for the therapeutic potential CCK-1 and GLP-1 pathways could be harnessed in a single fusion peptide, yielding a promising combination therapy strategy for treating metabolic disorders.