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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539594/ https://www.ncbi.nlm.nih.gov/pubmed/31064153 http://dx.doi.org/10.3390/molecules24091756 |
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author | Fedorczyk, Bartlomiej Lipiński, Piotr F. J. Puszko, Anna K. Tymecka, Dagmara Wilenska, Beata Dudka, Wioleta Perret, Gerard Y. Wieczorek, Rafal Misicka, Aleksandra |
author_facet | Fedorczyk, Bartlomiej Lipiński, Piotr F. J. Puszko, Anna K. Tymecka, Dagmara Wilenska, Beata Dudka, Wioleta Perret, Gerard Y. Wieczorek, Rafal Misicka, Aleksandra |
author_sort | Fedorczyk, Bartlomiej |
collection | PubMed |
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, 3, IC(50) = 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 3 and discuss the observed structure–activity relationships. |
format | Online Article Text |
id | pubmed-6539594 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-65395942019-05-31 Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165 Fedorczyk, Bartlomiej Lipiński, Piotr F. J. Puszko, Anna K. Tymecka, Dagmara Wilenska, Beata Dudka, Wioleta Perret, Gerard Y. Wieczorek, Rafal Misicka, Aleksandra Molecules Article 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, 3, IC(50) = 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 3 and discuss the observed structure–activity relationships. MDPI 2019-05-06 /pmc/articles/PMC6539594/ /pubmed/31064153 http://dx.doi.org/10.3390/molecules24091756 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Fedorczyk, Bartlomiej Lipiński, Piotr F. J. Puszko, Anna K. Tymecka, Dagmara Wilenska, Beata Dudka, Wioleta Perret, Gerard Y. Wieczorek, Rafal Misicka, Aleksandra Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165 |
title | 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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539594/ https://www.ncbi.nlm.nih.gov/pubmed/31064153 http://dx.doi.org/10.3390/molecules24091756 |
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