Rational design of dual peptides targeting ghrelin and Y2 receptors to regulate food intake and body weight

J Med Chem. 2015 May 28;58(10):4180-93. doi: 10.1021/jm501702q. Epub 2015 May 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Obesity Agents / chemistry
  • Anti-Obesity Agents / pharmacology*
  • Binding, Competitive
  • Body Weight / drug effects*
  • COS Cells
  • Chlorocebus aethiops
  • Drug Design
  • Eating / drug effects*
  • Female
  • Ghrelin*
  • Humans
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Molecular Targeted Therapy
  • Peptides / chemical synthesis
  • Peptides / chemistry*
  • Peptides / pharmacology*
  • Receptors, Gastrointestinal Hormone / agonists*
  • Receptors, Ghrelin / agonists
  • Receptors, Ghrelin / antagonists & inhibitors*

Substances

  • Anti-Obesity Agents
  • Ghrelin
  • Peptides
  • Receptors, Gastrointestinal Hormone
  • Receptors, Ghrelin
  • intestinal y2 receptor