Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165
Inhibiting 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...
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doaj-3d52b5c4efd74835b00c95b0979256dc2020-11-25T02:16:47ZengMDPI AGMolecules1420-30492019-05-01249175610.3390/molecules24091756molecules24091756Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165Bartlomiej Fedorczyk0Piotr F. J. Lipiński1Anna K. Puszko2Dagmara Tymecka3Beata Wilenska4Wioleta Dudka5Gerard Y. Perret6Rafal Wieczorek7Aleksandra Misicka8Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, PolandDepartment of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, PolandFaculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, PolandFaculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, PolandFaculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, PolandLaboratory of Cytometry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093 Warsaw, PolandUniversité Paris 13, Sorbonne Paris Cité, INSERM U1125, 74 rue Marcel Cachin, 93017 Bobigny, FranceFaculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, PolandFaculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, PolandInhibiting 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 μM concentration (the best compound Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg, <b>3</b>, IC<sub>50</sub> = 8.39 μM). 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 <b>3</b> and discuss the observed structure−activity relationships.https://www.mdpi.com/1420-3049/24/9/1756peptidomimeticsVEGF<sub>165</sub>neuropilin-1molecular dynamicsstructure–activity relationship |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Bartlomiej Fedorczyk Piotr F. J. Lipiński Anna K. Puszko Dagmara Tymecka Beata Wilenska Wioleta Dudka Gerard Y. Perret Rafal Wieczorek Aleksandra Misicka |
spellingShingle |
Bartlomiej Fedorczyk Piotr F. J. Lipiński Anna K. Puszko Dagmara Tymecka Beata Wilenska Wioleta Dudka Gerard Y. Perret Rafal Wieczorek Aleksandra Misicka Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165 Molecules peptidomimetics VEGF<sub>165</sub> neuropilin-1 molecular dynamics structure–activity relationship |
author_facet |
Bartlomiej Fedorczyk Piotr F. J. Lipiński Anna K. Puszko Dagmara Tymecka Beata Wilenska Wioleta Dudka Gerard Y. Perret Rafal Wieczorek Aleksandra Misicka |
author_sort |
Bartlomiej Fedorczyk |
title |
Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165 |
title_short |
Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165 |
title_full |
Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165 |
title_fullStr |
Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165 |
title_full_unstemmed |
Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165 |
title_sort |
triazolopeptides inhibiting the interaction between neuropilin-1 and vascular endothelial growth factor-165 |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2019-05-01 |
description |
Inhibiting 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 μM concentration (the best compound Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg, <b>3</b>, IC<sub>50</sub> = 8.39 μM). 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 <b>3</b> and discuss the observed structure−activity relationships. |
topic |
peptidomimetics VEGF<sub>165</sub> neuropilin-1 molecular dynamics structure–activity relationship |
url |
https://www.mdpi.com/1420-3049/24/9/1756 |
work_keys_str_mv |
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1724889072476880896 |