Biochemical and Structural Analysis of the Binding Determinants of a Vascular Endothelial Growth Factor Receptor Peptidic Antagonist

Cyclic peptide antagonist c[YYDEGLEE1-NH(2), which disrupts the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGERs), represents a promising tool in the fight against cancer and age-related macular degeneration. Furthermore, coupled to a cyclen derivative, this ligand could be used as a medicinal imaging agent. Nevertheless, before generating such molecular probes, son-le preliminary studies need to be undertaken in order to define the more suitable positions for introduction of the cyclen macrocycle. Through an Ala-scan study on this peptide, we identified its binding motif, and an NMR study highlights its binding sites on the VEGFR-1D2 Ig-like domain. Guided by the structural relationship results deduced from the effect of the peptides on endothelial cells, new peptides were synthesized and grafted on beads. Used in a pull-down assay, these new peptides trap the VEGFRs, thus confirming that the identified amino acid positions are suitable for further derivatization.