Leukocyte-function associated antigen-1 (LFA-1) is an αLβ2 chain integrin expressed on the surface of endothelial cells that modulates the behavior of leukocytes by mediating their adhesion to other cells through its interaction to cell-surface ligands. The most important ligand of LFA-1 is ICAM-1 which is expressed on the surface of endothelial cells. The interaction between LFA-1 and ICAM-1 is involved in inflammatory responses and is therefore implicated in inflammatory pathologies and autoimmune diseases; and, in addition, it is involved in many cancer processes. In light of this, there is great interest in developing small molecule, orally available, inhibitors of the LFA-1/ICAM-1 interaction. A structurally diverse collection of small molecule inhibitors has been characterized and developed either to bind the IDAS site of the αL I-domain or to the MIDAS of the β2 I-like domain. In this review, a summary of the structure and regulation of LFA-1 will be given, followed by a description of the different classes of inhibitors that have been described to date.
Keywords: LFA-1, ICAM-1, integrin, cell adhesion, inhibitors, allosteric inhibitors, protein-protein interaction
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