Targeting αvβ3 Integrin: Design and Applications of Mono- and Multifunctional RGD-Based Peptides and Semipeptides

Abstract

The outstanding physio-pathological role played by integrin receptors in living subjects motivates the enormous interest shown by scientists worldwide for this topic. More than twenty years of research has spanned across the structural and functional elucidation of these proteins and over their antagonism-based biomedical applications. The proof-of concept stage, aimed at identifying potent inhibitors, covered a decade of studies, and paved the way for a more advanced era of research where these antagonist molecules were thrown into the deep end of applicative studies. This review intends to summarize the major efforts conducted thus far and focuses on the design, synthesis and biomedical applications of cyclic RGD-containing alpha(v)beta(3) integrin antagonists, in both their small and macromolecular formats. In particular, Chapters 1 and 2 offer a comprehensive outlook on the rational basis for the design of integrin inhibitors, Chapter 3 chronicles the biological and medical applications of monofunctional RGD integrin ligands both in their monomeric and multimeric asset, and Chapter 4 illustrates the potential of RGD-based multifunctional systems in molecular medicine.

Synthesis and Biological Evaluation of RGD Peptidomimetic–Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

“…To deeply investigate the potential of this drug-targeting strategy, we synthesized three SMDCs (6)(7)(8) [a] With consideration of RGD-drug conjugates for which enough literature data are available (that is, IC 50 values for the free drug and the RGD-drug conjugate against a v b 3 + and a v b 3 À cancer cells), a value of TI = 9.0 is the highest ever reported. [28] However, this value is much lower than those exhibited by ADCs (TI % 1000-2000).…”

“…[5] Extracellular matrix (ECM) proteins bind to a v b 3 integrin through the Arg-Gly-Asp (RGD) tripeptide sequence. [6] Several peptides and peptidomimetics bearing the RGD sequence have been reported to show high affinity for the receptor, [7] and the structural basis for this recognition was provided by a v b 3 -integrin cocrystallization with the cyclopentapeptide Cilengitide. [8] Due to their ability to selectively bind integrin receptors, RGD ligands have been conjugated to a number of cytotoxic agents (for example, doxorubicin, [9,10] doxsaliform, [11] monomethylauristatin E, [12] camptothecin, [13] cisplatin, [14] paclitaxel [15] ) and to proapoptotic compounds, [16,17] with the aim to target these drugs at integrin-rich tumor tissues.…”

Sialic Acid Associated with αvβ3 Integrin Mediates HIV-1 Tat Protein Interaction and Endothelial Cell Proangiogenic Activation

“…Thus, besides neuraminidases, sialyltransferases may also be involved in the regulation of angiogenesis. Fourth, integrin ␣ v ␤ 3 is a target for antitumor therapies based on antibodies or RGD-based compounds that prevent the interaction of the integrin with its proangiogenic ligands (58). The ␣ v ␤ 3 antagonist activity of MAA points to NeuAc-binding lectins as templates for the design of novel integrin antagonists endowed with antiangiogenic potential.…”

Cyclic isoDGR Peptidomimetics as Low‐Nanomolar αvβ3 Integrin Ligands

“…Many peptide and peptidomimetic integrin ligands have been developed that contain the RGD tripeptide sequence with different flanking residues and three-dimensional presentation. [3] Recently, our group reported a new class of cyclic RGD peptidomimetics (Figure 1), containing bifunctional diketopiperazine (DKP) scaffolds, formally derived from 2,3-diaminopropionic acid and aspartic acid and differing in the configuration of the two DKP stereocenters and in the substitution at the DKP nitrogen atoms.…”