Integrins avb3, avb5 and a5b1, key mediators of cell adhesion, differentiation, proliferation, angiogenesis and tumor growth, have been considered very promising targets for theranostic application. Due to the similarity of the RGD binding regions in these integrins, the development of synthetic molecules with high activity and selectivity for the different subtypes is a tricky goal to pursue. The majority of the ligands described so far as selective integrin targeting has in fact residual, yet significant, affinity for the other integrins, thus stimulating extensive research to develop novel integrin specific molecules.
In 2006 our research group designed by rational approach, in collaboration with IC-CNR, and synthesized the first avb3 selective peptide, referred as RGDechi, a chimeric molecule encompassing a cyclic portion containing the RGD triade for integrin binding and a linear sequence derived from the C-terminal fragment of the echistatin protein to confer specificity for b3 subunit. RGDechi was opportunely labelled and deeply characterized both in preclinical in vitro and in vivo cancer models. In order to improve its enzymatic stability and pharmacokinetic properties, chemical modifications were also introduced.NMR studies and computational analyses on cell membranes overexpressing avb3 integrin, performed in collaboration with University of Campania Luigi Vanvitelli, allowed the full understanding of avb3/RGDechi recognition mechanism. All biological and structural information collected in the years about RGDechi prompted us to consider this peptide as progenitor for the development of new peptides selective for different integrin subtypes, including avb5 and a5b1.
- Del Gatto, A. et al. Novel and selective alpha(v)beta(3) receptor peptide antagonist: Design, synthesis, and biological behavior. J Med Chem 2006, 49, 3416. doi: 10.1021/jm060233m
- Comegna, D. et al. Chemical Modification for Proteolytic Stabilization of the Selective alpha(v)beta(3) Integrin RGDechi Peptide: in Vitro and in Vivo Activities on Malignant Melanoma Cells. J Med Chemv 2017, 60, 9874. doi: 10.1021/acs.jmedchem.7b01590
- Capasso, D. et al. Selective Targeting of alpha v beta 5 Integrin in HepG2 Cell Line by RGDechi15D Peptide. Molecules 2020, 25. doi: 10.3390/molecules25184298
- Hill, B.S. et al. Therapeutic Potential of a Novel alpha(v)beta(3) Antagonist to Hamper the Aggressiveness of Mesenchymal Triple Negative Breast Cancer Sub-Type. Cancers 2019, 11. doi: 10.3390/cancers11020139
- Bolzati, C. et al. [Tc-99m][Tc(N)PNP43]-Labeled RGD Peptides As New Probes for a Selective Detection of alpha v beta(3) Integrin: Synthesis, Structure-Activity and Pharmacokinetic Studies. J Med Chem 2018, 61, 9596. doi: 10.1021/acs.jmedchem.8b01075
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