Title:Progress in Small Molecule and Biologic Therapeutics Targeting Ghrelin Signaling
Volume: 16
Issue: 6
Author(s): Kayleigh R. McGovern, Joseph E. Darling and James L. Hougland
Affiliation:
Keywords:
Diabetes, ghrelin, ghrelin O-acyltransferase, GHS-R1a receptor, membrane-bound O-acyltransferase, obesity,
Prader-Willi syndrome, spiegelmer.
Abstract: Ghrelin is a circulating peptide hormone involved in regulation of a wide array of
physiological processes. As an endogenous ligand for growth hormone secretagogue receptor (GHSR1a),
ghrelin is responsible for signaling involved in energy homeostasis, including appetite
stimulation, glucose metabolism, insulin signaling, and adiposity. Ghrelin has also been implicated in
modulation of several neurological processes. Dysregulation of ghrelin signaling is implicated in
diseases related to these pathways, including obesity, type II diabetes, and regulation of appetite and
body weight in patients with Prader-Willi syndrome. Multiple steps in the ghrelin signaling pathway
are available for targeting in the development of therapeutics for these diseases. Agonists and
antagonists of GHS-R1a have been widely studied and have shown varying levels of effectiveness within ghrelin-related
physiological pathways. Agents targeting ghrelin directly, either through depletion of ghrelin levels in circulation or
inhibitors of ghrelin O-acyltransferase whose action is required for ghrelin to become biologically active, are receiving
increasing attention as potential therapeutic options. We discuss the approaches utilized to target ghrelin signaling and
highlight the current challenges toward developing small-molecule agents as potential therapeutics for ghrelin-related
diseases.
