Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists.

In the recent decades, great progress has been made in the development of ghrelin receptor ligands. The discovery of the first in vitro only active peptide growth hormone secretagogue derived from Met-enkephalin was the foundation for later discoveries of the receptor and the endogenous ligand ghrelin. Since then, the scope of peptides, peptidomimetics, and small-molecules targeting the ghrelin receptor, GHS-R1a, has expanded dramatically. Numerous agonists have been tested in animals and several in humans, and a handful have progressed to clinical trials for indications such as growth hormone release, gastric emptying, and cachexia. However, with the exception of the approval of GHRP-2 for diagnostic purposes in Japan, none of the candidates have been successfully introduced into the market. More recently, the attention of researchers has been concentrated on developing antagonists and inverse agonists for pharmacological treatment of the ever-expanding obese and overweight population. In this review, we describe the development of GHS-R1a targeting agonists, antagonists, and inverse agonists. We focus on current and completed clinical trials and the therapeutic potential of currently available ligands.

Peptides binding to the hunger hormone ghrelin.

The neutralisation of circulating ghrelin, the only known peripheral orexigenic peptide hormone, is a promising approach for the pharmacological treatment of obesity. To select peptides with an affinity towards ghrelin, 4 selection procedures were carried out with random peptide phage display libraries Ph.D.-7 and Ph.D.-12. Due to the absence of a common consensus motif, a stepwise elimination approach was used. The pool of selected peptides displaying phage clones was thoroughly examined to remove any potential target-unrelated peptides. The affinity of the remaining phage clones for ghrelin was tested with ELISA. An analysis of the binding properties revealed four-phage displayed peptides that bind to ghrelin with moderate affinity, with ADTVPRH and MEMKKTHPVLGA being the most specific. Additional advantage of peptide MEMKKTHPVLGA is an indication of binding to octanoyl group on N-terminal part of ghrelin, involved in receptor interaction. Hence peptide MEMKKTHPVLGA represents the most suitable lead for further investigation.