Identification of GDF15 peptide fragments inhibiting GFRAL receptor signaling

Flora Alexopoulou, Nina Buch-Månson, Søren Ljungberg Pedersen, Niels Vrang, Lisbeth Nielsen Fink, Kristian Strømgaard*

*Corresponding author for this work

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1 Citation (Scopus)
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Abstract

Growth differentiation factor 15 (GDF15) is believed to be a major causative factor for cancer-induced cachexia. Recent elucidation of the central circuits involved in GDF15 function and its signaling through the glial cell-derived neurotrophic factor family receptor α-like (GFRAL) has prompted the interest of targeting the GDF15-GFRAL signaling for energy homeostasis and body weight regulation. Here, we applied advanced peptide technologies to identify GDF15 peptide fragments inhibiting GFRAL signaling. SPOT peptide arrays revealed binding of GDF15 C-terminal peptide fragments to the extracellular domain of GFRAL. Parallel solid-phase peptide synthesis allowed for generation of complementary GDF15 peptide libraries and their subsequent functional evaluation in cells expressing the GFRAL/RET receptor complex. We identified a series of C-terminal fragments of GDF15 inhibiting GFRAL activity in the micromolar range. These novel GFRAL peptide inhibitors could serve as valuable tools for further development of peptide therapeutics towards the treatment of cachexia and other wasting disorders.

Original languageEnglish
Article number171063
JournalPeptides
Volume168
Number of pages7
ISSN0196-9781
DOIs
Publication statusPublished - 2023

Bibliographical note

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© 2023 The Authors

Keywords

  • Cachexia
  • GDF15
  • GFRAL
  • Peptide inhibitors
  • Peptide technologies

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