Extending Foldamer Design beyond α-Helix Mimicry: α/β-Peptide Inhibitors of Vascular Endothelial Growth Factor Signaling

Diverse strategies have been explored to mimic the surface displayed by an a-helical segment of a protein, with the goal of creating inhibitors of helix-mediated protein-protein interactions. Many recognition surfaces on proteins, however, are topologically more complex and less regular than a single alpha-helix. We describe efforts to develop peptidic foldamers that bind to the irregular receptor-recognition surface of vascular endothelial growth factor (VEGF). Our approach begins with a 19-residue a-peptide previously reported by Fairbrother et al. (Biochemistry 1998, 37, 17754) to bind to this surface on VEGF. Systematic evaluation of alpha ->beta replacements throughout this 19-mer sequence enabled us to identify homologues that contain up to similar to 30% beta residues, retain significant affinity for VEGF, and display substantial resistance to proteolysis. These alpha/beta-peptides can block VEGF-stimulated proliferation of human umbilical vein endothelial cells.