Urea moiety as amide bond mimetic in peptide-like inhibitors of VEGF-A165/NRP-1 complex

Bioorg Med Chem Lett. 2019 Sep 1;29(17):2493-2497. doi: 10.1016/j.bmcl.2019.07.016. Epub 2019 Jul 10.

Abstract

NRP-1 is an important co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2). Many reports suggested that NRP-1 might also serve as a separate receptor for VEGF-A165 causing stimulation of tumour growth and metastasis. Therefore, compounds interfering with VEGF-A165/NRP-1 complex triggered interest in the design of new molecules, including peptides, as anti-angiogenic and anti-tumour drugs. Here, we report the synthesis, affinity and stability evaluation of the urea-peptide hybrids, based on general Lys(hArg)-AA2-AA3-Arg sequence, where hArg residue was substituted by Arg urea unit. Such substitution does not substantially affected affinity of compounds for NRP-1 but significantly increased their proteolytic stability in plasma.

Keywords: Amide bond mimetic; Neuropilin-1; Peptidomimetics; Protein–ligand interaction; VEGF-A(165).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Drug Design
  • Half-Life
  • Humans
  • Neuropilin-1 / antagonists & inhibitors*
  • Neuropilin-1 / metabolism
  • Peptidomimetics / chemistry*
  • Peptidomimetics / metabolism
  • Protein Binding
  • Urea / chemistry*
  • Urea / metabolism
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Amides
  • Antineoplastic Agents
  • Peptidomimetics
  • Vascular Endothelial Growth Factor A
  • Neuropilin-1
  • Urea