The tripeptide sequence arginine-glycine-aspartate (RGD) has been identified as the common motif used by several endogenous ligands to recognize and bind a group of integrins, including aVb3 and aIIb3. The integrin aVb3 has a key role in angiogenesis and tumor progression while aIIb3 is the most abundant platelet surface receptor that mediates platelet aggregation. The context of the ligand RGD sequence (flanking residues, three-dimensional presentation) and individual features of the integrin binding pockets determine the recognition specificity and discrimination ability, i.e. whether a productive interaction occurs. The X-ray structures of both integrin receptors with an RGD cyclopeptide were reported, revealing how the RGD is recognized by the two integrins. Many research groups have investigated the use of conformationally constrained cyclic RGD peptides and peptidomimetics as active and selective inhibitors for both receptors. Recently, we investigated the conformational preferences of cyclic peptidomimetics containing diketopiperazine (DKP) scaffolds by NMR spectroscopy and computational analysis.Due to the conformational constraints introduced by the cyclic system and by the rigid scaffold, the peptide backbone is forced to adopt only few geometries depending on the absolute and relative stereochemistry of the diketopiperazine. To elucidate, on the molecular basis, the structural requirements for binding to αVβ3 and aIIb3, docking studies were performed starting from the representative conformations of RGD peptidomimetics.STD and trNOESY studies of ligand interactions with αVβ3 in ECV304 (bladder cancer cells) living cells and with aIIb3 in platelets nicely agree with the docking models.

Targeting integrins alphaVbeta3 and alphaIIbeta3 with RGD peptidomimetics : study of the ligand conformation and of the ligand-receptor interactions / M. Civera, L. Belvisi, C. Gennari, U. Piarulli, D. Potenza, F. Vasile. ((Intervento presentato al 8. convegno European workshop in drug design tenutosi a Siena nel 2011.

Targeting integrins alphaVbeta3 and alphaIIbeta3 with RGD peptidomimetics : study of the ligand conformation and of the ligand-receptor interactions

M. Civera
Primo
;
L. Belvisi
Secondo
;
C. Gennari;D. Potenza
Penultimo
;
F. Vasile
Ultimo
2011

Abstract

The tripeptide sequence arginine-glycine-aspartate (RGD) has been identified as the common motif used by several endogenous ligands to recognize and bind a group of integrins, including aVb3 and aIIb3. The integrin aVb3 has a key role in angiogenesis and tumor progression while aIIb3 is the most abundant platelet surface receptor that mediates platelet aggregation. The context of the ligand RGD sequence (flanking residues, three-dimensional presentation) and individual features of the integrin binding pockets determine the recognition specificity and discrimination ability, i.e. whether a productive interaction occurs. The X-ray structures of both integrin receptors with an RGD cyclopeptide were reported, revealing how the RGD is recognized by the two integrins. Many research groups have investigated the use of conformationally constrained cyclic RGD peptides and peptidomimetics as active and selective inhibitors for both receptors. Recently, we investigated the conformational preferences of cyclic peptidomimetics containing diketopiperazine (DKP) scaffolds by NMR spectroscopy and computational analysis.Due to the conformational constraints introduced by the cyclic system and by the rigid scaffold, the peptide backbone is forced to adopt only few geometries depending on the absolute and relative stereochemistry of the diketopiperazine. To elucidate, on the molecular basis, the structural requirements for binding to αVβ3 and aIIb3, docking studies were performed starting from the representative conformations of RGD peptidomimetics.STD and trNOESY studies of ligand interactions with αVβ3 in ECV304 (bladder cancer cells) living cells and with aIIb3 in platelets nicely agree with the docking models.
22-mag-2011
Settore CHIM/06 - Chimica Organica
Università di Siena
Targeting integrins alphaVbeta3 and alphaIIbeta3 with RGD peptidomimetics : study of the ligand conformation and of the ligand-receptor interactions / M. Civera, L. Belvisi, C. Gennari, U. Piarulli, D. Potenza, F. Vasile. ((Intervento presentato al 8. convegno European workshop in drug design tenutosi a Siena nel 2011.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/167097
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