Inhibitors targeting the LFA-1/ICAM-1 cell-adhesion interaction: design and mechanism of action.
Leukocyte-function associated antigen-1 (LFA-1) is an alpha(L)beta(2) 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 alpha(L) I-domain or to the MIDAS of the beta2 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.
Zimmerman
Tahl
T
Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, Edificio 800, 48160 Derio, Spain.
Blanco
Francisco J
FJ
D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology*; D015195:Drug Design; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D011485:Protein Binding
D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1