Novel peptides selected to bind vascular endothelial growth factor target the receptor-binding site

Peptides that inhibit binding of vascular endothelial growth factor (VEGF) to its receptors, KDR and Fit-1, have been produced using phage display. Li braries of short disulfide-constrained peptides yielded three distinct clas ses of peptides that bind to the receptor-binding domain of VEGF with micro molar affinities. The highest affinity peptide was also shown to antagonize VEGF-induced proliferation of primary human umbilical vascular endothelial cells. The peptides bind to a region of VEGF known to contain the contact surface for Flt-1 and the functional determinants for KDR binding. This sug gests that the receptor-binding region of VEGF is a binding "hot spot" that is readily targeted by selected peptides and supports earlier assertions t hat phage-derived peptides frequently target protein-protein interaction si tes. Such peptides may lead to the development of pharmacologically useful VEGF antagonists.