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Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165

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cris.lastimport.scopus2024-02-12T20:10:51Z
dc.abstract.enInhibiting the interaction of neuropilin-1 (NRP-1) with vascular endothelial growth factor (VEGF) has become an interesting mechanism for potential anticancer therapies. In our previous works, we have obtained several submicromolar inhibitors of this interaction, including branched pentapeptides of general structure Lys(Har)-Xxx-Xxx-Arg. With the intent to improve the proteolytic stability of our inhibitors, we turned our attention to 1,4-disubstituted 1,2,3-triazoles as peptide bond isosteres. In the present contribution, we report the synthesis of 23 novel triazolopeptides along with their inhibitory activity. The compounds were synthesized using typical peptide chemistry methods, but with a conversion of amine into azide completely on solid support. The inhibitory activity of the synthesized derivatives spans from 9.2\% to 58.1\% at 10 M concentration (the best compound Lys(Har)-Gly[Trl]Gly[Trl]Arg, 3, IC50 = 8.39 M). Synthesized peptidotriazoles were tested for stability in human plasma and showed remarkable resistance toward proteolysis, with half-life times far exceeding 48 h. In vitro cell survival test resulted in no significant impact on bone marrow derived murine cells 32D viability. By means of molecular dynamics, we were able to propose a binding mode for compound 3 and discuss the observed structure-activity relationships.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorMisicka-Kęsik, Aleksandra
dc.contributor.authorPuszko, Anna
dc.contributor.authorLipiński, Piotr
dc.contributor.authorDudka, Wioleta
dc.contributor.authorPerret, Gerard Y.
dc.contributor.authorTymecka, Dagmara
dc.contributor.authorWileńska, Beata
dc.contributor.authorWieczorek, Rafał
dc.contributor.authorFedorczyk, Bartłomiej
dc.date.accessioned2024-01-26T11:06:44Z
dc.date.available2024-01-26T11:06:44Z
dc.date.copyright2019-05-06
dc.date.issued2019
dc.description.accesstimeAT_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number9
dc.description.versionFINAL_PUBLISHED
dc.description.volume24
dc.identifier.doi10.3390/MOLECULES24091756
dc.identifier.issn1420-3049
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/123800
dc.identifier.weblinkhttps://www.mdpi.com/1420-3049/24/9/1756
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofMolecules
dc.relation.pages1756
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.enpeptidomimetics
dc.subject.enVEGF(165)
dc.subject.enneuropilin-1
dc.subject.enmolecular dynamics
dc.subject.enstructure-activity relationship
dc.titleTriazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165
dc.typeJournalArticle
dspace.entity.typePublication