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

Abstract

Ghrelin and Y2 receptors play a central role in appetite regulation inducing opposite effects. The Y2 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 lead 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 Y2 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 Y2 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.

Structure–Activity Study of Ghrelin(1–8) Resulting in High Affinity Fluorine-Bearing Ligands for the Ghrelin Receptor

“…Beck-Sickinger et al have studied 68 Ga-labeled ghrelin(1–28) and ghrelin(1–16) analogues as potential PET agents. Although they exhibit similar efficacy for the ghrelin receptor as per native ghrelin based upon an inositol phosphate turnover assay, they were found to have rapid blood clearance and suboptimal metabolic stability, especially for the truncated analogues. − In order to increase the stability of the developed ghrelin(1–8) analogues, bioisosteres can be added to reduce degradation by endopeptidases and exopeptidases. Bioisosteres are chemical groups that possess similar physical and chemical properties as another chemical compound and elicit similar biological properties .…”

C‐terminus of a hexapeptidic ghrelin receptor inverse agonist can switch peptide behavior from inverse agonism to agonism

“…Cells were subsequently washed with ice‐cold PBS (Lonza). Obtained values were normalized to no competition (1% BSA/H 2 O or 10 −11 M ghrelin) and full competition (10 −6 M ghrelin) …”

Development of a ghrelin receptor inverse agonist for positron emission tomography

“…In vivo imaging of the Ghrelin receptor should help to improve our understanding of its mode of action and might become a powerful tool for diagnosis and drug development [26,34]. So far, only few groups tried to develop probes for PET and optical imaging of Ghrelin receptors [26,[35][36][37][38][39][40]. In particular the group of Lewis and colleagues started the research and development of PET radiotracers for imaging of the Ghrelin receptor [26,37,38,41].…”