Integrins are a family of adhesion molecules which regulate diverse cell functions. Recent studies provide evidence of the importance of Arg-Gly-Asp (RGD) binding integrins in tumor angiogenesis, progression and metastasis, suggesting the use of dual- and multi-antagonists to target tumor progression [1]. The most common strategy to inhibit integrin function consists in blocking the binding of the natural RGD ligand by small-molecule mimics. A large number of cyclic peptidic and peptidomimetic ligands have been developed, showing high affinity and specificity [2]. Extending this approach, we have recently reported a small library of cyclic peptidomimetics containing a bifunctional diketopiperazine scaffold and the tripeptide sequence RGD as potent αvβ3 integrin ligands [3]. These ligands have shown binding inhibition also for α5β1 in competition with biotinylated fibronectin. We studied at molecular detail the interaction between our RGD mimics and a suspension of MDA-MB-231 breast cancer cells (in which integrin α5β1 is highly expressed), by applying bioaffinity NMR techniques (including Saturation Transfer Difference and transferred NOE). The results were compared with the NMR data obtained for the same compounds in presence of ECV304 bladder cancer cells [4] in which integrin αvβ3 is mainly expressed. For each compound, the free and bound conformation and the epitope were identified in presence of the two cell lines. The NMR data were interpreted with the aid of docking calculations of the RGD ligands in the crystal structures of the α5β1 and αvβ3 binding sites, providing an improved understanding of ligand–integrin interactions and explaining the different behavior of the same compound in presence of the two integrins.

Different behavior of cyclic RGD peptidomimetics versus a5b1 and aVb3 integrin-rich cancer cells: NMR and computational analysis / F. Vasile, M. Civera, D. Arosio, L. Belvisi, C. Gennari, U. Piarulli, D. Potenza. ((Intervento presentato al convegno Synthesis and biomedical applications of tumor-targeting peptidomimetics tenutosi a Bologna nel 2016.

Different behavior of cyclic RGD peptidomimetics versus a5b1 and aVb3 integrin-rich cancer cells: NMR and computational analysis

F. Vasile
Primo
;
M. Civera
Secondo
;
L. Belvisi;C. Gennari;D. Potenza
Ultimo
2016

Abstract

Integrins are a family of adhesion molecules which regulate diverse cell functions. Recent studies provide evidence of the importance of Arg-Gly-Asp (RGD) binding integrins in tumor angiogenesis, progression and metastasis, suggesting the use of dual- and multi-antagonists to target tumor progression [1]. The most common strategy to inhibit integrin function consists in blocking the binding of the natural RGD ligand by small-molecule mimics. A large number of cyclic peptidic and peptidomimetic ligands have been developed, showing high affinity and specificity [2]. Extending this approach, we have recently reported a small library of cyclic peptidomimetics containing a bifunctional diketopiperazine scaffold and the tripeptide sequence RGD as potent αvβ3 integrin ligands [3]. These ligands have shown binding inhibition also for α5β1 in competition with biotinylated fibronectin. We studied at molecular detail the interaction between our RGD mimics and a suspension of MDA-MB-231 breast cancer cells (in which integrin α5β1 is highly expressed), by applying bioaffinity NMR techniques (including Saturation Transfer Difference and transferred NOE). The results were compared with the NMR data obtained for the same compounds in presence of ECV304 bladder cancer cells [4] in which integrin αvβ3 is mainly expressed. For each compound, the free and bound conformation and the epitope were identified in presence of the two cell lines. The NMR data were interpreted with the aid of docking calculations of the RGD ligands in the crystal structures of the α5β1 and αvβ3 binding sites, providing an improved understanding of ligand–integrin interactions and explaining the different behavior of the same compound in presence of the two integrins.
feb-2016
Settore CHIM/06 - Chimica Organica
Different behavior of cyclic RGD peptidomimetics versus a5b1 and aVb3 integrin-rich cancer cells: NMR and computational analysis / F. Vasile, M. Civera, D. Arosio, L. Belvisi, C. Gennari, U. Piarulli, D. Potenza. ((Intervento presentato al convegno Synthesis and biomedical applications of tumor-targeting peptidomimetics tenutosi a Bologna nel 2016.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/387783
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