A novel class of low molecular weight ligands of αvβ₃ and α₅β₁ integrins, that possess a dehydro-β-amino acid as conformationally constrained core, linked to the pharmacophoric moieties mimicking the RGD recognition sequence, have been synthesized through a very simple protocol. Cell adhesion assays and integrin-mediated signaling activation experiments suggested a good affinity of these compounds toward both integrin receptors. Moreover, further elongation with two glycine units allowed to obtain an excellent dual inhibitor. Structural models for αvβ₃ integrin-ligand binding confirmed that the dehydro-β-amino derivatives are able to act as an electrostatic clamp by establishing several stabilizing interactions with the receptor.
Keywords: Cell adhesion; Dehydro-β-amino acids; Drug discovery; Peptidomimetic; Signaling.
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