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

Growth differentiation factor 15 (GDF15) is a contributorto nausea,emesis, and anorexia following chemotherapy via binding to the GFRAL-RETreceptor complex expressed in hindbrain neurons. Therefore, GDF15-mediatedGFRAL-RET signaling is a promising target for improving treatmentoutcomes for chemotherapy patients. We developed peptide-based antagonistsof GFRAL that block GDF15-mediated RET recruitment. Our initial libraryscreen led to five novel peptides. Surface plasmon resonance and flowcytometric analyses of the most efficacious of this group, termedGRASP, revealed its capacity to bind to GFRAL. In vivo studies in rats revealed that GRASP could attenuate GDF15-inducednausea and anorexia resulting from cisplatin. Combined with Ondansetron,GRASP led to an even greater attenuation of the anorectic effectsof cisplatin compared to either agent alone. Our results highlightthe beneficial effects of GRASP as an agent to combat chemotherapy-inducedmalaise. GRASP may also be effective in other conditions associatedwith elevated levels of GDF15.