Extending foldamer design beyond ?-helix mimicry: ?/?-peptide inhibitors of vascular endothelial growth factor signaling.

ABSTRACT: Diverse strategies have been explored to mimic the surface displayed by an ?-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 ?-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 ?-peptide previously reported by Fairbrother et al. (Biochemistry 1998, 37, 17754) to bind to this surface on VEGF. Systematic evaluation of ??? replacements throughout this 19-mer sequence enabled us to identify homologues that contain up to ~30% ? residues, retain significant affinity for VEGF, and display substantial resistance to proteolysis. These ?/?-peptides can block VEGF-stimulated proliferation of human umbilical vein endothelial cells.

SUBMITTER: Haase HS 

PROVIDER: S-EPMC3551614 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature