Modulation of αvβ3- and α5β1-integrin-mediated adhesion by dehydro-β-amino acids containing peptidomimetics

• Dehydro-β-amino acid derivatives were synthesized as RGD mimetics.
• Cell adhesion assays suggested good affinity toward αvβ3 and α5β1 integrins.
• Selected compounds showed ability to inhibit integrin-mediated signaling activation.
• Docking experiments were performed to verify ligand–receptor interactions.
• The low molecular weight and the simple synthetic route may represent an advantage on other ligands.

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.

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