Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays a critical role in tumor growth and metastasis and VEGF inhibition has been actively investigated as a potential anticancer therapy. We have been investigating structure-based modifications of known VEGF-binding peptides in an attempt to improve their affinity. The phage-derived VEGF-binding peptide is a disulfide-constrained 19-mer (VEPNCDIHVMWEWECFERL) [1]. Previous studies indicated that these peptides have defined solution structures upon binding to VEGF and that a short helical fragment at the peptide C-terminus (EWECFERL) is critical for its binding [2]. We have examined whether enhanced interactions could be induced between the trapping peptides and VEGF by extending the peptides at their C-termini. A series of two and four residues were added to the end of the helical fragment generating an amphipathic helical pattern. We found that the modified peptides gained a 2-8 fold increase over the original motif in inhibition of the interaction between VEGF and its receptor.
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