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Branched pentapeptides as potent inhibitors of the vascular endothelial growth factor 165 binding to Neuropilin-1: Design, synthesis and biological activity

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dc.abstract.enThe demonstrated involvement of VEGF(165)/NRP-1 complex in pathological angiogenesis has catalyzed interest in blocking this interaction to combat angiogenesis dependent diseases. It was shown before that Lys-Pro-Pro-Arg is a fairly strong inhibitor of the VEGF(165)/NRP-1 interaction. Our current findings suggest that the side chain elongation of the Lysl by branching it with additional homoarginine (Har) residue, to obtain Lys(Har)-Pro-Pro-Arg, allows more effective inhibition. Moreover, increasing the flexibility of the middle part of molecule, in particular with simultaneous introduction of additional interacting elements at the second or third position, produced compounds up to 30-fold more active (IC50 = 0.2 1.1M) than the heptapeptide ATWLPPR (A7R) which is one of the first peptide known as an effective antagonist of the VEGF(165) binding to NRP-1 and in vivo decreases breast cancer angiogenesis and growth. Herein, we present also the structure-activity study of Lys(Har)-Pro-Pro-Arg, discussing the design, synthesis, inhibitory activity, proteolytic stability and molecular modeling of the prepared derivatives. For two of the most active analogs the high proteolytic stability was also observed. These studies provide the next step for elucidating the optimal structure of the small peptidic inhibitors of VEGF(165)/NRP-1 interaction that could serve as research tools or be prospective drug candidates. (C) 2018 Elsevier Masson SAS. All rights reserved.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorMisicka-Kęsik, Aleksandra
dc.contributor.authorPuszko, Anna
dc.contributor.authorLipiński, Piotr
dc.contributor.authorPerret, Gerard Y.
dc.contributor.authorTymecka, Dagmara
dc.contributor.authorWileńska, Beata
dc.contributor.authorSura, Karolina
dc.contributor.authorFedorczyk, Bartłomiej
dc.date.accessioned2024-01-24T18:54:51Z
dc.date.available2024-01-24T18:54:51Z
dc.date.issued2018
dc.description.financeNie dotyczy
dc.description.volume158
dc.identifier.doi10.1016/J.EJMECH.2018.08.083
dc.identifier.issn0223-5234
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/102508
dc.identifier.weblinkhttps://www.sciencedirect.com/science/article/pii/S0223523418307566?via%3Dihub
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofEuropean Journal of Medicinal Chemistry
dc.relation.pages453-462
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.subject.enNeuropilin-1
dc.subject.enVEGF(165)
dc.subject.enNeuropilin/VEGF(165) binding inhibition
dc.subject.enStructure-activity relationship
dc.subject.enPeptide biostability
dc.titleBranched pentapeptides as potent inhibitors of the vascular endothelial growth factor 165 binding to Neuropilin-1: Design, synthesis and biological activity
dc.typeJournalArticle
dspace.entity.typePublication