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Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting α(v)β(3) Integrin and VEGF Receptors**
A dual-action ligand targeting both integrin α(V)β(3) and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic α(V)β(3) Arg-Gly-Asp (RGD) ligand with a decapentapeptide. The latter was obtained from a known VEGFR antagonist by acetylation...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Ltd
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608532/ https://www.ncbi.nlm.nih.gov/pubmed/26491644 http://dx.doi.org/10.1002/open.201500062 |
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author | Zanella, Simone Mingozzi, Michele Dal Corso, Alberto Fanelli, Roberto Arosio, Daniela Cosentino, Marco Schembri, Laura Marino, Franca De Zotti, Marta Formaggio, Fernando Pignataro, Luca Belvisi, Laura Piarulli, Umberto Gennari, Cesare |
author_facet | Zanella, Simone Mingozzi, Michele Dal Corso, Alberto Fanelli, Roberto Arosio, Daniela Cosentino, Marco Schembri, Laura Marino, Franca De Zotti, Marta Formaggio, Fernando Pignataro, Luca Belvisi, Laura Piarulli, Umberto Gennari, Cesare |
author_sort | Zanella, Simone |
collection | PubMed |
description | A dual-action ligand targeting both integrin α(V)β(3) and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic α(V)β(3) Arg-Gly-Asp (RGD) ligand with a decapentapeptide. The latter was obtained from a known VEGFR antagonist by acetylation at the Lys13 side chain. Functionalization of the precursor ligands was carried out in solution and in the solid phase, affording two fragments: an alkyne VEGFR ligand and the azide integrin α(V)β(3) ligand, which were conjugated by click chemistry. Circular dichroism studies confirmed that both the RGD and VEGFR ligand portions of the dual-action compound substantially adopt the biologically active conformation. In vitro binding assays on isolated integrin α(V)β(3) and VEGFR-1 showed that the dual-action conjugate retains a good level of affinity for both its target receptors, although with one order of magnitude (10/20 times) decrease in potency. The dual-action ligand strongly inhibited the VEGF-induced morphogenesis in Human Umbilical Vein Endothelial Cells (HUVECs). Remarkably, its efficiency in preventing the formation of new blood vessels was similar to that of the original individual ligands, despite the worse affinity towards integrin α(V)β(3) and VEGFR-1. |
format | Online Article Text |
id | pubmed-4608532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | John Wiley & Sons, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-46085322015-10-21 Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting α(v)β(3) Integrin and VEGF Receptors** Zanella, Simone Mingozzi, Michele Dal Corso, Alberto Fanelli, Roberto Arosio, Daniela Cosentino, Marco Schembri, Laura Marino, Franca De Zotti, Marta Formaggio, Fernando Pignataro, Luca Belvisi, Laura Piarulli, Umberto Gennari, Cesare ChemistryOpen Full Papers A dual-action ligand targeting both integrin α(V)β(3) and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic α(V)β(3) Arg-Gly-Asp (RGD) ligand with a decapentapeptide. The latter was obtained from a known VEGFR antagonist by acetylation at the Lys13 side chain. Functionalization of the precursor ligands was carried out in solution and in the solid phase, affording two fragments: an alkyne VEGFR ligand and the azide integrin α(V)β(3) ligand, which were conjugated by click chemistry. Circular dichroism studies confirmed that both the RGD and VEGFR ligand portions of the dual-action compound substantially adopt the biologically active conformation. In vitro binding assays on isolated integrin α(V)β(3) and VEGFR-1 showed that the dual-action conjugate retains a good level of affinity for both its target receptors, although with one order of magnitude (10/20 times) decrease in potency. The dual-action ligand strongly inhibited the VEGF-induced morphogenesis in Human Umbilical Vein Endothelial Cells (HUVECs). Remarkably, its efficiency in preventing the formation of new blood vessels was similar to that of the original individual ligands, despite the worse affinity towards integrin α(V)β(3) and VEGFR-1. John Wiley & Sons, Ltd 2015-10 2015-07-02 /pmc/articles/PMC4608532/ /pubmed/26491644 http://dx.doi.org/10.1002/open.201500062 Text en © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Full Papers Zanella, Simone Mingozzi, Michele Dal Corso, Alberto Fanelli, Roberto Arosio, Daniela Cosentino, Marco Schembri, Laura Marino, Franca De Zotti, Marta Formaggio, Fernando Pignataro, Luca Belvisi, Laura Piarulli, Umberto Gennari, Cesare Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting α(v)β(3) Integrin and VEGF Receptors** |
title | Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting α(v)β(3) Integrin and VEGF Receptors** |
title_full | Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting α(v)β(3) Integrin and VEGF Receptors** |
title_fullStr | Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting α(v)β(3) Integrin and VEGF Receptors** |
title_full_unstemmed | Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting α(v)β(3) Integrin and VEGF Receptors** |
title_short | Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting α(v)β(3) Integrin and VEGF Receptors** |
title_sort | synthesis, characterization, and biological evaluation of a dual-action ligand targeting α(v)β(3) integrin and vegf receptors** |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608532/ https://www.ncbi.nlm.nih.gov/pubmed/26491644 http://dx.doi.org/10.1002/open.201500062 |
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