Peptides Targeting GDNF Family Receptor Alpha 1 (GFRα1) Mimic Glial Cell Line-Derived Neurotrophic Factor (GDNF) Bioactivity

Glial cell line-derived neurotrophic factor (GDNF) is a neuroprotective protein with widespread applications in regenerative medicine, though its clinical translation has been limited. Peptide mimetics have the potential to overcome the limitations associated with the translation of GDNF. Herein, peptides targeting the GDNF receptor GFRα1 were identified by screening a 12-mer linear peptide phage display library against GFRα1. Peptide hits were rationalized by computational alanine scanning mutagenesis studies to identify residues contributing to GDNF and GFRα1 binding. Four hit peptides were synthesized and tested for GFRα1 binding affinity. All peptides activated the downstream phosphatidylinositol 3 kinase signaling pathway in SH-SY5Y cells and increased cellular proliferation. The biological activity of two peptides matched that of recombinant GDNF, as measured by neurite outgrowth of primary dorsal root ganglion neurons. For the first time, we report monomeric GFRα1-targeting peptides that mimic the biological effects of GDNF, with potential applications in regenerative medicine.