Innovative integrin ligands as multifunctional therapeutic tools: from inflammation and cancer to the pathophysiological role of αvβ6 in idiopathic pulmonary fibrosis

Integrins are heterodimeric receptors involved in cell adhesion and bidirectional signaling, with key roles in inflammation, fibrosis, tissue remodelling, and cancer. This work focused on the pharmacological and functional characterization of novel synthetic peptidomimetic ligands targeting several integrins (α4β1, αMβ2, αVβ6, and αVβ8), aiming both to identify new therapeutic candidates and to deepen the understanding of integrin-driven pathological mechanisms.A first library of α/β-hybrid LDV-based compounds showed potent and selective antagonism toward α4β1 integrin. Among sixteen molecules, three displayed significant binding affinity and effectively inhibited downstream signaling pathways, including ERK, Akt, and JNK, supporting their potential as scaffolds for anti-inflammatory and anti-cancer drug development. A second library of β-lactam-based compounds, initially designed as α4β1 ligands, provided insights into structure–activity relationships governing leukocyte integrin recognition. Notably, four compounds unexpectedly exhibited high affinity for αMβ2, leading to the identification of MC183 as a potent αMβ2 antagonist with marked anti-inflammatory activity, capable of reducing pro-inflammatory cytokine expression and inhibiting neutrophil transendothelial migration. A third class of theranostic ligands, combining fluorescent and cytotoxic moieties and targeting α4β1-overexpressing tumor cells, showed favorable cytotoxic profiles across multiple cancer cell lines, although selective integrin-mediated internalization was not observed. In parallel, Amp-based cyclic peptidomimetics selectively targeting αVβ6 and αVβ8 demonstrated differential effects on colorectal cancer cell viability and migration, highlighting their promise as anti-tumor and anti-metastatic agents. Finally, functional studies on basal epithelial cells from IPF lung tissue revealed a key role for αVβ6 in epithelial migration, as blocking this integrin significantly reduced cell motility, suggesting dynamic integrin–ECM reprogramming during fibrosis progression. Overall, this work supports integrins as valuable translational targets in inflammation, fibrosis, and cancer.