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Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting αvβ3 Integrin and VEGF Receptors.

Zanella S, Mingozzi M, Dal Corso A, Fanelli R, Arosio D, Cosentino M, Schembri L, Marino F, De Zotti M, Formaggio F, Pignataro L, Belvisi L, Piarulli U, Gennari C - ChemistryOpen (2015)

Bottom Line: In vitro binding assays on isolated integrin αVβ3 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 αVβ3 and VEGFR-1.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Chimica, Università degli Studi di Milano Via C. Golgi 19, 20133, Milan, Italy.

ABSTRACT
A dual-action ligand targeting both integrin αVβ3 and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic αVβ3 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 αVβ3 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 αVβ3 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 αVβ3 and VEGFR-1.

No MeSH data available.


The preferred intramolecular hydrogen-bonded pattern proposed for compound 1 on the basis of NMR spectroscopic data. The arrow indicates a significant nuclear Overhauser effect (NOE) contact. Computational studies assessed that more than 90 % of the conformations sampled during restrained mixed-mode Metropolis Monte Carlo/Stochastic Dynamics simulations adopted an extended arrangement of the RGD sequence characterized by a pseudo-β-turn type II at DKP−Arg and the formation of the corresponding hydrogen bond between the NH−Gly and C(5)=O.
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fig06: The preferred intramolecular hydrogen-bonded pattern proposed for compound 1 on the basis of NMR spectroscopic data. The arrow indicates a significant nuclear Overhauser effect (NOE) contact. Computational studies assessed that more than 90 % of the conformations sampled during restrained mixed-mode Metropolis Monte Carlo/Stochastic Dynamics simulations adopted an extended arrangement of the RGD sequence characterized by a pseudo-β-turn type II at DKP−Arg and the formation of the corresponding hydrogen bond between the NH−Gly and C(5)=O.

Mentions: In a previous work, this class of compounds was already demonstrated via NMR and computational studies to adopt a β-turn-like conformation (Figure 6).6


Synthesis, Characterization, and Biological Evaluation of a Dual-Action Ligand Targeting αvβ3 Integrin and VEGF Receptors.

Zanella S, Mingozzi M, Dal Corso A, Fanelli R, Arosio D, Cosentino M, Schembri L, Marino F, De Zotti M, Formaggio F, Pignataro L, Belvisi L, Piarulli U, Gennari C - ChemistryOpen (2015)

The preferred intramolecular hydrogen-bonded pattern proposed for compound 1 on the basis of NMR spectroscopic data. The arrow indicates a significant nuclear Overhauser effect (NOE) contact. Computational studies assessed that more than 90 % of the conformations sampled during restrained mixed-mode Metropolis Monte Carlo/Stochastic Dynamics simulations adopted an extended arrangement of the RGD sequence characterized by a pseudo-β-turn type II at DKP−Arg and the formation of the corresponding hydrogen bond between the NH−Gly and C(5)=O.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608532&req=5

fig06: The preferred intramolecular hydrogen-bonded pattern proposed for compound 1 on the basis of NMR spectroscopic data. The arrow indicates a significant nuclear Overhauser effect (NOE) contact. Computational studies assessed that more than 90 % of the conformations sampled during restrained mixed-mode Metropolis Monte Carlo/Stochastic Dynamics simulations adopted an extended arrangement of the RGD sequence characterized by a pseudo-β-turn type II at DKP−Arg and the formation of the corresponding hydrogen bond between the NH−Gly and C(5)=O.
Mentions: In a previous work, this class of compounds was already demonstrated via NMR and computational studies to adopt a β-turn-like conformation (Figure 6).6

Bottom Line: In vitro binding assays on isolated integrin αVβ3 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 αVβ3 and VEGFR-1.

View Article: PubMed Central - PubMed

Affiliation: Dipartimento di Chimica, Università degli Studi di Milano Via C. Golgi 19, 20133, Milan, Italy.

ABSTRACT
A dual-action ligand targeting both integrin αVβ3 and vascular endothelial growth factor receptors (VEGFRs), was synthesized via conjugation of a cyclic peptidomimetic αVβ3 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 αVβ3 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 αVβ3 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 αVβ3 and VEGFR-1.

No MeSH data available.