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

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cris.lastimport.scopus2024-02-12T20:24:52Z
dc.abstract.enNeuropilin-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.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorLepelletier, Yves
dc.contributor.authorHopfgartner, Gérard
dc.contributor.authorRignault-Bricard, Rachel
dc.contributor.authorHermine, Olivier
dc.contributor.authorPuszko, Anna
dc.contributor.authorSosnowski, Piotr
dc.contributor.authorPułka-Ziach, Karolina
dc.contributor.authorMisicka-Kęsik, Aleksandra
dc.date.accessioned2024-01-26T11:28:46Z
dc.date.available2024-01-26T11:28:46Z
dc.date.copyright2020-12-23
dc.date.issued2021
dc.description.accesstimeAT_PUBLICATION
dc.description.financeŚrodki finansowe przyznane na realizację projektu w zakresie badań naukowych lub prac rozwojowych
dc.description.number1
dc.description.versionFINAL_PUBLISHED
dc.description.volume22
dc.identifier.doi10.3390/IJMS22010072
dc.identifier.issn1422-0067
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/124333
dc.identifier.weblinkhttps://www.mdpi.com/1422-0067/22/1/72/pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.relation.pages72
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.enpeptidomimetics
dc.subject.enamide bond mimetic
dc.subject.enneuropilin-1
dc.subject.enVEGF-A165
dc.subject.enprotein–ligand interaction
dc.titleUrea-Peptide Hybrids as VEGF-A165/NRP-1 Complex Inhibitors with Improved Receptor Affinity and Biological Properties
dc.typeJournalArticle
dspace.entity.typePublication