Urea-Peptide Hybrids as VEGF-A<sub>165</sub>/NRP-1 Complex Inhibitors with Improved Receptor Affinity and Biological Properties
2021
Anna K. Puszko | Piotr Sosnowski | Rachel Rignault-Bricard | Olivier Hermine | Gérard Hopfgartner | Karolina Pułka-Ziach | Yves Lepelletier | Aleksandra Misicka
Neuropilin-1 (NRP-1), the major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2), may also independently act with VEGF-A<sub>165</sub> to stimulate tumour growth and metastasis. Therefore, there is great interest in compounds that can block VEGF-A165/NRP-1 interaction. Peptidomimetic type inhibitors represent a promising strategy in the treatment of NRP-1-related disorders. Here, we present the synthesis, affinity, enzymatic stability, molecular modeling and in vitro binding evaluation of the branched urea–peptide hybrids, based on our previously reported Lys(hArg)-Dab-Oic-Arg active sequence, where the Lys(hArg) branching has been modified by introducing urea units to replace the peptide bond at various positions. One of the resulting hybrids increased the affinity of the compound for NRP-1 more than 10-fold, while simultaneously improving resistance for proteolytic stability in serum. In addition, ligand binding to NRP-1 induced rapid protein stock exocytotic trafficking to the plasma membrane in breast cancer cells. Examined properties characterize this compound as a good candidate for further development of VEGF<sub>165</sub>/NRP-1 inhibitors.
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