New peptides structurally related to VEGF-A ₁₆₅ exon-7 and -8 encoded domains antagonize its binding to NRP-1 and VEGF-R1

We report in the present study the design, synthesis and preliminary biological evaluations of linear, short-sized, and polymeric peptides as VEGF-A₁₆₅ binding to NRP-1 and/or VEGF-R1 antagonists. These newly-synthesized peptides are structurally related to the VEGF-A₁₆₅ domains encoded by exon-7 and -8. Thus, the key role of exon-7 encoded cysteine residues, and the relevance of the C-terminal peptide chemical function (amide or acid) were demonstrated. Indeed, COOH-terminal peptides showed a good selectivity for NRP-1, while CONH₂-terminal peptides did not. Taking advantage of these results, we designed original VEGF-A₁₆₅ binding to NRP-1 and VEGF-R1 polymeric peptide antagonists, which showed potent HUVEC anti-proliferative activity. Finally, this work paved the way for the design of future therapeutics targeting the VEGF-A₁₆₅ angiogenic signaling pathway.