Urea-Peptide Hybrids as VEGF-A165/NRP-1 Complex Inhibitors with Improved Receptor Affinity and Biological Properties
| Autor: | Olivier Hermine, Anna K. Puszko, Rachel Rignault-Bricard, Karolina Pulka-Ziach, Yves Lepelletier, Gérard Hopfgartner, Aleksandra Misicka, Piotr Sosnowski |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Molecular model Peptidomimetic Peptide VEGF-A165 01 natural sciences Catalysis Inorganic Chemistry lcsh:Chemistry 03 medical and health sciences chemistry.chemical_compound Neuropilin 1 amide bond mimetic Peptide bond Physical and Theoretical Chemistry Receptor Molecular Biology lcsh:QH301-705.5 Spectroscopy chemistry.chemical_classification 010405 organic chemistry Organic Chemistry General Medicine 0104 chemical sciences Computer Science Applications Vascular endothelial growth factor 030104 developmental biology Enzyme neuropilin-1 chemistry Biochemistry lcsh:Biology (General) lcsh:QD1-999 protein–ligand interaction peptidomimetics |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 72, p 72 (2021) International Journal of Molecular Sciences Volume 22 Issue 1 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | 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&ndash 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. |
| Databáze: | OpenAIRE |
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