Creation of a Peptide Antagonist of the GFRAL-RET Receptor Complex for the Treatment of GDF15-Induced Malaise

J Med Chem. 2023 Aug 24;66(16):11237-11249. doi: 10.1021/acs.jmedchem.3c00667. Epub 2023 Jul 28.

Abstract

Growth differentiation factor 15 (GDF15) is a contributor to nausea, emesis, and anorexia following chemotherapy via binding to the GFRAL-RET receptor complex expressed in hindbrain neurons. Therefore, GDF15-mediated GFRAL-RET signaling is a promising target for improving treatment outcomes for chemotherapy patients. We developed peptide-based antagonists of GFRAL that block GDF15-mediated RET recruitment. Our initial library screen led to five novel peptides. Surface plasmon resonance and flow cytometric analyses of the most efficacious of this group, termed GRASP, revealed its capacity to bind to GFRAL. In vivo studies in rats revealed that GRASP could attenuate GDF15-induced nausea and anorexia resulting from cisplatin. Combined with Ondansetron, GRASP led to an even greater attenuation of the anorectic effects of cisplatin compared to either agent alone. Our results highlight the beneficial effects of GRASP as an agent to combat chemotherapy-induced malaise. GRASP may also be effective in other conditions associated with elevated levels of GDF15.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anorexia / metabolism
  • Cell Membrane / metabolism
  • Cisplatin / therapeutic use
  • Growth Differentiation Factor 15* / antagonists & inhibitors
  • Growth Differentiation Factor 15* / metabolism
  • Growth Differentiation Factor 15* / pharmacology
  • Rats

Substances

  • Cisplatin
  • Growth Differentiation Factor 15