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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.

Original publication

DOI

10.1160/TH03-02-0106

Type

Journal article

Journal

Thromb Haemost

Publication Date

09/2003

Volume

90

Pages

501 - 510

Keywords

Amino Acid Sequence, Angiogenesis Inhibitors, Binding Sites, Dose-Response Relationship, Drug, Drug Stability, Endothelium, Vascular, Humans, Neovascularization, Physiologic, Peptides, Phosphorylation, Structure-Activity Relationship, Umbilical Veins, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2