Abstract
Arg-Gly-Asp (RGD)-binding integrins, e.g., αvβ3, αvβ1, αvβ5 integrins, are currently regarded as privileged targets for the delivery of diagnostic and theranostic agents, especially in cancer treatment. In contrast, scarce attention has been paid so far to the diagnostic opportunities promised by integrins that recognize other peptide motifs. In particular, α4β1 integrin is involved in inflammatory, allergic, and autoimmune diseases, therefore, it represents an interesting therapeutic target. Aiming at obtaining simple, highly stable ligands of α4β1 integrin, we designed hybrid α/β peptidomimetics carrying linkable side chains for the expedient functionalization of biomaterials, nano- and microparticles. We identified the prototypic ligands MPUPA-(R)-isoAsp(NHPr)-Gly-OH (12) and MPUPA-Dap(Ac)-Gly-OH (13) (MPUPA, methylphenylureaphenylacetic acid; Dap, 2,3-diamino propionic acid). Modification of 12 and 13 by introduction of flexible linkers at isoAsp or Dap gave 49 and 50, respectively, which allowed for coating with monolayers (ML) of flat zeolite crystals. The resulting peptide–zeolite MLs were able to capture selectively α4β1 integrin-expressing cells. In perspective, the α4β1 integrin ligands identified in this study can find applications for preparing biofunctionalized surfaces and diagnostic devices to control the progression of α4β1 integrin-correlated diseases.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Moving from the α/β-hybrid lead 6 (Figure 1), we designed a series of analogues (Figure 2) containing diverse β-amino acid cores, while maintaining glycine as the C-terminal residue and the diphenylurea moiety MPUPA (Figure 2)
Leukocyte migration is typical of autoimmune diseases characterized by chronic inflammation, e.g., rheumatoid arthritis, autoimmune encephalomyelitis, and multiple sclerosis [53]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Integrins are one of the major families of adhesion receptors that mediate cell–cell and cell–extracellular matrix interactions (ECM). These heterodimeric transmembrane proteins are composed by diverse α and β subunits, giving rise in mammals to 24 possible α/β heterodimers [1]. Integrins, expressed on many cell types, regulate fundamental functions, such as adhesion, signaling, and viability, but they are deeply involved in a variety of diseases, including the initiation and progression of cancer, coronary diseases, inflammatory, and autoimmune pathologies. Antibodies (Ab) or small molecules that block integrin functions have attracted significant attention as potential drugs [2]
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