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Published on: September 30, 2019
Identification of GDF15 peptide fragments inhibiting GFRAL receptor signaling
Flora Alexopoulou1, Nina Buch-Månson2, Søren Ljungberg Pedersen2
1Gubra Aps, Hørsholm, DK-2970 Hørsholm, Denmark; Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
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.
Insights
Researchers identified Growth Differentiation Factor 15 (GDF15) peptide fragments that inhibit GDF15-GFRAL signaling. These novel inhibitors offer potential therapeutic strategies for treating cancer-induced cachexia and other wasting disorders.
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Growth Differentiation Factor 15 (GDF15) is a key factor in cancer-induced cachexia.
- GDF15 signaling via the GFRAL receptor regulates energy homeostasis and body weight.
- Targeting the GDF15-GFRAL pathway presents a therapeutic opportunity for wasting disorders.
Purpose of the Study:
- To identify GDF15 peptide fragments that inhibit GFRAL signaling.
- To explore novel therapeutic agents for cachexia and wasting conditions.
Main Methods:
- Utilized advanced peptide technologies, including SPOT peptide arrays.
- Synthesized GDF15 peptide libraries via solid-phase peptide synthesis.
- Evaluated functional activity in cells expressing the GFRAL/RET receptor complex.
Main Results:
- Identified GDF15 C-terminal peptide fragments that bind to the extracellular domain of GFRAL.
- Discovered several GDF15 peptide fragments inhibiting GFRAL activity at micromolar concentrations.
- Confirmed the inhibitory effect of these novel peptide fragments on GFRAL signaling.
Conclusions:
- Novel GDF15 peptide inhibitors of GFRAL signaling were successfully identified.
- These peptide inhibitors represent promising tools for developing therapeutics against cachexia.
- Further development of these inhibitors could lead to treatments for various wasting disorders.
