Lily Bauer
Syracuse University
Development of an Allosteric Peptide Antagonist of the GFRAL-RET Receptor Complex
Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine expressed in a variety of tissues and secreted into circulation during diverse stress and disease states, including cancer and anticancer chemotherapy. GDF15 signals through the heterodimeric glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL)-RET receptor complex. Although GDF15-GFRAL signaling was initially investigated as a therapeutic target for obesity, early results showed activation of this pathway were likely to produce illness-like behaviors, including anorexia, nausea, body weight loss, and cachexia. Using computational modeling, high-throughput peptide synthesis, in vitro receptor-binding assays, and functional luciferase-based assays in HEK293T cells expressing GFRAL and RET, we designed and validated a long-acting orthosteric peptide antagonist of GFRAL-RET. In vivo administration produced marked dose-dependent attenuation of GDF15-induced nausea and body weight loss in rats. These findings support the potential of long-acting allosteric peptide antagonists to inhibit GFRAL-RET signaling and reinforce further development of this approach for mitigating GDF15-mediated adverse effects associated with cancer and chemotherapy
Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine expressed in a variety of tissues and secreted into circulation during diverse stress and disease states, including cancer and anticancer chemotherapy. GDF15 signals through the heterodimeric glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL)-RET receptor complex. Although GDF15-GFRAL signaling was initially investigated as a therapeutic target for obesity, early results showed activation of this pathway were likely to produce illness-like behaviors, including anorexia, nausea, body weight loss, and cachexia. Using computational modeling, high-throughput peptide synthesis, in vitro receptor-binding assays, and functional luciferase-based assays in HEK293T cells expressing GFRAL and RET, we designed and validated a long-acting orthosteric peptide antagonist of GFRAL-RET. In vivo administration produced marked dose-dependent attenuation of GDF15-induced nausea and body weight loss in rats. These findings support the potential of long-acting allosteric peptide antagonists to inhibit GFRAL-RET signaling and reinforce further development of this approach for mitigating GDF15-mediated adverse effects associated with cancer and chemotherapy
