Curr Pharm Des. 2008;14(22):2128-39.

Inhibitors targeting the LFA-1/ICAM-1 cell-adhesion interaction: design and mechanism of action.

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Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia, Edificio 800, 48160 Derio, Spain.

Abstract

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.

PMID:: 18781967; [PubMed - indexed for MEDLINE]

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The I domain of integrin leukocyte function-associated antigen-1 is involved in a conformational change leading to high affinity binding to ligand intercellular adhesion molecule 1 (ICAM-1). [J Biol Chem. 1998]
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