title: Extending foldamer design beyond α-helix mimicry: α/β-peptide inhibitors of vascular endothelial growth factor signaling.
abstract: Diverse strategies have been explored to mimic the surface displayed by an α-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 α-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 α-peptide previously reported by Fairbrother et al. (Biochemistry 1998, 37, 17754) to bind to this surface on VEGF. Systematic evaluation of α→β replacements throughout this 19-mer sequence enabled us to identify homologues that contain up to ~30% β residues, retain significant affinity for VEGF, and display substantial resistance to proteolysis. These α/β-peptides can block VEGF-stimulated proliferation of human umbilical vein endothelial cells.
authors.affiliation: Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
authors.forename: Holly S
authors.initials: HS
authors.lastname: Haase
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Peterson-Kaufman
authors.forename: Sheeny K
authors.initials: SK
authors.lastname: Lan Levengood
authors.forename: James W
authors.initials: JW
authors.lastname: Checco
authors.forename: William L
authors.initials: WL
authors.lastname: Murphy
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D000595:Amino Acid Sequence; D049109:Cell Proliferation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010455:Peptides; D042461:Vascular Endothelial Growth Factor A