Structure-activity relationship study of a small cyclic peptide H-c[Lys-Pro-Glu]-Arg-OH: a potent inhibitor of Vascular Endothelial Growth Factor interaction with Neuropilin-1

Bioorg Med Chem. 2017 Jan 15;25(2):597-602. doi: 10.1016/j.bmc.2016.11.024. Epub 2016 Nov 14.

Abstract

Inhibition of angiogenesis is one of the most promising approaches in anticancer therapy. It was recently suggested that Neuropilin-1 (NRP-1) in tumour cells may serve as a separate receptor for Vascular Endothelial Growth Factor-165 (VEGF165) which is one of the main pro-angiogenic agents in the organism. Therefore molecules inhibiting VEGF165 binding to NRP-1 could be potential candidates for new antiangiogenic and anticancer drugs. Here we present a structure-activity relationship study of the peptide H-c[Lys-Pro-Glu]-Arg-OH which showed high inhibitory effect on VEGF165/NRP-1 binding (IC50=0.18μM) in our previous study. We report the design, synthesis, in vitro assays and docking analysis of four small cyclic peptides (14-,15-membered ring) and one bigger cyclic compound (30-membered ring). Our study shows that both the ring size and configuration of amino acid residues present in the structure are crucial for high inhibitory effect.

Keywords: A7R; Angiogenesis; Cyclic peptides; Docking analysis; NRP-1; VEGF(165).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / chemistry
  • Angiogenesis Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Neovascularization, Pathologic / drug therapy*
  • Neuropilin-1 / antagonists & inhibitors*
  • Neuropilin-1 / metabolism
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factors / antagonists & inhibitors*
  • Vascular Endothelial Growth Factors / metabolism

Substances

  • Angiogenesis Inhibitors
  • Peptides, Cyclic
  • Vascular Endothelial Growth Factors
  • Neuropilin-1