Targeting alphaVbeta3 Integrins: Design, Synthesis and Applications of Mono- and Multifunctional RGD-Based Paseudipeptides.

Targeting alphaVbeta3 Integrins: Design, Synthesis and Applications of Mono- and Multifunctional RGD-Based Pseudopeptides Franca Zanardi, Dipartimento Farmaceutico, Università degli Studi di Parma, Parco Area delle Scienze 27A, 43124 Parma, Italy e-mail: franca.zanardi@unipr.it Since their early discovery a quarter century ago, integrins have increasingly become the converging focus of a multitude of studies and experimentations aimed at elucidating their structure, function, and biological regulation.1 The alphaVbeta3 integrin family, in particular, has been elected as a compelling molecular indicator of tumor angiogenesis and tumor progression, invasion and metastasis, since they are overexpressed on proliferating endothelial cells as well as various tumor-related cells.2 Accordingly, a large number of specific, highly potent alphaVbeta3-addressing small molecule ligands have been designed and implemented so far, which contain or mimic the key receptor-recognizing RGD tripeptide motif.3 This lecture intends to summarize the major efforts conducted in the field and focuses on the design, synthesis and biomedical applications of cyclic RGD-containing pseudopeptide binders which selectively target the alphaVbeta3 integrins. Emblematic examples will be given, ranging from monovalent and monofunctional small-molecule integrin antagonists, to last-generation mono/multifunctional constructs where appropriate cytotoxic and/or imaging cargos are consigned to active alphaVbeta3-directing (pseudo)peptide vectors under the shape of highly integrated small molecule or nanosized, molecular or supramolecular platforms.