In cancer, some specific cell surface receptors, such as integrins aVb3, aVb5 and a5b1 and the growth factor receptors (e.g. VEGFRs), play a key role in tumor angiogenesis, progression and metastasis. Tumor cell proliferation is regulated by the activity of these receptors, through the formation of specific protein-protein complexes. Physical interaction of integrins with growth factor receptors (“cross-talk”) gives rise to synergistic effects. In vivo evidence of VEGFR2/aVb3 association has been provided, revealing co-localization of these receptors on endothelial cells of proliferating blood vessels, although the exact nature of the complex containing aVb3 and the VEGFRs is still unclear. Moreover, a dual-specific engineered protein able to bind both VEGFR2 and integrin aVb3 inhibited angiogenic processes in vitro and in vivo. Our research group developed a potent aVb3 integrin ligand, which consists of a cyclic RGD peptidomimetic containing a diketopiperazine scaffold functionalized for further conjugation with other molecular devices. Recently, a short helical peptide (15 aminoacid residues) was reported that selectively binds to the extracellular domain of VEGFR1 receptor and exhibits anti-angiogenic activity in vivo. Starting from these two selective ligands, we synthesized a covalently-linked dual-specific agent, aiming at inhibiting both aVb3 and VEGFR1. This compound was prepared through microwaveassisted solid-phase peptide synthesis, with a final “click” reaction between the alkynebearing solid-supported VEGFR1 ligand and the azido-functionalized PEG8-RGD integrin ligand. We are currently in vitro testing the anti-angiogenic activity of the dual-action ligand in VEGF165 - induced capillary tube formation experiments (HUVEC cells), in comparison with the singularly administered and the co-administered ligands. The intertwined relationship between VEGFRs and aVb3 integrin suggests that a dualspecific agent capable of inhibiting both receptors would offer interesting therapeutic potential.
|Titolo:||Dual-action ligand targeting both integrin αvβ3 and VEGF receptors|
|Data di pubblicazione:||giu-2013|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Citazione:||Dual-action ligand targeting both integrin αvβ3 and VEGF receptors / M. Mingozzi, A. Dal Corso, S. Zanella, R. Fanelli, L. Belvisi, L. Pignataro, U. Piarulli, C. Gennari. ((Intervento presentato al 5. convegno European Conference on Chemistry for Life Sciences tenutosi a Barcelona nel 2013.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|