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

Autor: Borner T; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States., Tinsley IC; Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States., Milliken BT; Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States., Doebley SA; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States., Najjar NR; Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States., Kerwood DJ; Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States., De Jonghe BC; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States., Hayes MR; Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States., Doyle RP; Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States.; Departments of Medicine and Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York 13245, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2023 Aug 24; Vol. 66 (16), pp. 11237-11249. Date of Electronic Publication: 2023 Jul 28.
DOI: 10.1021/acs.jmedchem.3c00667
Abstrakt: 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.
Databáze: MEDLINE
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