Identification of Peptidic Antagonists of Vascular Endothelial Growth Factor Receptor 1 by Scanning the Binding Epitopes of Its Ligands

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Abstract
Cancer angiogenesis is mainly initiated by vascular endothelial growth factors (VEGFs). On the basis of the reported crystal structures of three natural ligands (VEGF-A, -B, and PlGF) with the major receptors VEGFR-1 and VEGFR-2, we scanned receptor-binding epitopes of these ligands by designing linear and cyclic peptides with the aim to disrupt the VEGF-A/VEGFR-1 interaction, which is implicated in cancer development. The ability of peptides to inhibit this interaction was evaluated by an ELISA-based assay. Several peptides, especially those mimicking loop 1 (L1) of these ligands that binds primarily to domain D3 of VEGFRs, have demonstrated higher inhibition for VEGF-A/VEGFR-1 binding. They have also shown inhibitory effects on VEGF-induced tube formation in HUVECs (human umbilical vein endothelial cells). These results validate the domain D3 of VEGFRs as an efficient target for the design of VEGFR antagonists.
Funding Information
  • Agence Nationale de la Recherche (ANR-2010-Blanc-1533-03, ANR-2015-CE17-0005-04)
  • Centre National de la Recherche Scientifique
  • China Scholarship Council
  • Universit? Paris Descartes

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