Rational Design of Dual Peptides Targeting Ghrelin and Y2 Receptors to Regulate Food Intake and Body Weight

Ghrelin and Y-2 receptors play a central role in appetite regulation inducing opposite effects: The Y-2 receptor induces satiety, while the ghrelin receptor promotes hunger and weight gain. However, the food regulating system is tightly controlled by interconnected pathways where redundancies can dead to poor efficacy and drug tolerance when addressing a single molecule. We developed a multitarget strategy to synthesize dual peptides simultaneously inhibiting the ghrelin receptor and stimulating the Y-2 receptor. Dual peptides showed dual activity in vitro, and one compound induced a slight diminution of food intake in a rodent model Of Obesity. In addition, stability studies in rats revealed different behaviors between the dual peptide and its corresponding monomers. The Y-2 receptor agonist was unstable in blood, while the dual peptide showed an intermediate stability compared to that of the highly stable ghrelin receptor inverse agonist.