Urea-Peptide Hybrids as VEGF-A165/NRP-1 Complex Inhibitors with Improved Receptor Affinity and Biological Properties

Abstract

Neuropilin-1 (NRP-1), the major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2), may also independently act with VEGF-A165 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 VEGF165/NRP-1 inhibitors.

Novel Compounds Targeting Neuropilin Receptor 1 with Potential To Interfere with SARS-CoV-2 Virus Entry

“…The assay was performed as described previously. 92 Plates (96-well, Nunc Maxisorp; Thermo Fisher Scientific, Waltham, MA, USA) were coated with human Neuropilin-1-Fc (200 ng per well, catalog no. 50-101-8343, Fisher, Hampton, NH) and incubated at 4 °C overnight.…”

Functional recovery of myocardial infarction by specific EBP‐PR1P peptides bridging injectable cardiac extracellular matrix and vascular endothelial growth factor

“…However, VEGF had not been translated into successful clinical trials, one of the important reasons was its rapid diffusion and short half‐life in the blood circulation, which led to low medication efficiency of VEGF. In recent years, the application of targeted peptides had been developed, which provided a new strategy for the treatment of ischemic diseases 39 …”

Advances in hybrid peptide-based self-assembly systems and their applications

“…52 More recently, a systematic study of α-amino acid replacement by a urea unit was carried out by Misicka et al One of the hybrid peptides had shown a 12-fold increase in the affinity towards Neuropilin-1 (NRP-1) as well as prolonged half-life against enzymatic cleavage. 256…”

“…52 More recently, a systematic study of α-amino acid replacement by a urea unit was carried out by Misicka et al One of the hybrid peptides had shown a 12-fold increase in the affinity towards Neuropilin-1 (NRP-1) as well as prolonged half-life against enzymatic cleavage. 256 A cationic urea-based cell-penetrating peptidomimetic conjugated with a cell-surface expressed nucleolin (NCL) pseudopeptide ligand for gene delivery purposes was synthesized by Guichard et al This hybrid heterodimer showed high potential in delivering plasmid-DNA to several human cells such as HEK293 and MRC5-V2 cells, and remarkable gene carrying capacity. Furthermore, this second-generation hybrid system exhibited non-cytotoxic features on MDA-MB-231 cells.…”