Engineering peptides in angiogenesis

he design of new peptides (QK) targeting two protein systems deeply involved in angiogenesis: integrins and vascular endothelial growth factor receptors is presented. Integrins are cell surface receptors that mediate adhesion of endothelial cells to the extracellular matrix and to the adjacent cells through the interaction with Arg-Gly-Asp (RGD) sequence found within many extracellular matrix protein (i.e. vitronectin). It was shown that integrin avb3 together with avb5 are overexpressed on tumor cells and endothelial cells of the tumor neovasculature, acting as angiogenic markers. It is of great therapeutic and diagnostic interest to develop new compds. able to discriminate between avb3 and avb5. NMR anal. revealed that QK adopts a helical conformation in water, whereas the peptide corresponding to the helix region of VEGF (VEGF15) is unstructured. The conformation of the designed peptide exactly corresponds to the N-terminal helix of VEGF when complexed with Flt-1. Binding studies showed that QK competes with VEGF for a binding site on EC membranes and activates both receptors similarly to VEGF. VEGF15 do not bind to the receptors indicating that the helical structure is necessary for the biol. activity. Cells proliferation expts. and the downstream activation of VEGF-dependent intracellular pathway (ERK1/2) confirmed the agonist behavior of the peptide. Results indicate that QK peptide is able to recapitulate many of the features in signal transduction that are reported for VEGF. The new peptide-based mols. reported may represent the lead compds. for the development of novel angiogenesis modulating drugs for application in diagnostic and targeted therapy