title: Potent inhibition of angiogenesis by D,L-peptides derived from vascular endothelial growth factor receptor 2.
abstract: Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells and plays a central role in angiogenesis and vasculogenesis. Therefore, VEGF and its receptors VEGFR-1 and VEGFR-2 are prime targets for anti-angiogenic intervention which is thought to be one of the most promising approaches in cancer therapy. Recently, we have discovered a VEGFR-2-derived peptide ((247)RTELNVGIDFNWEYP(261)) representing a potential binding site to VEGF. Using the spot synthesis technique, systematic D-amino acid substitutional analyses of this peptide were conducted and the resulting D,L-peptides inhibit VEGF binding to VEGFR-2 at half maximal concentration of 30 nM. The serum-stable D,L-peptides further inhibited autophosphorylation of the VEGFR-2 at nanomolar concentrations. Testing of the peptides in a spheroid-based angiogenesis assay demonstrated a potent anti-angiogenic effect in vitro. The rational design of potent and stable anti-angiogenic peptide inhibitors from their parent receptors provides a feasible route to develop novel leads for anti-angiogenic medicines.
authors.affiliation: Cytos Biotechnology AG, Zurich, Switzwerland. germeroth@iba-go.de
authors.forename: Christine
authors.initials: C
authors.lastname: Piossek
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Thierauch
authors.forename: Jens
authors.initials: J
authors.lastname: Schneider-Mergener
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer-Engert
authors.forename: Martin F
authors.initials: MF
authors.lastname: Bachmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Korff
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Lothar
authors.initials: L
authors.lastname: Germeroth
mesh_terms: D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2