Lymphocyte function-associated antigen 1(LFA-1)

Lymphocyte function-associated antigen 1(LFA-1) is part of the family of leukocyte integrins that are recognised by their common β-chains (β2, CD18). It is found on all T-cells and also on B-cells, macrophages and neutrophils and is involved in recruitment to the site of infection. It binds to ICAM-1 on antigen-presenting cells and functions as an adhesion molecule. It is the first to bind T-cells to antigen-presenting cells and initially binds weakly.

1025967-78-5
Lifitegrast
1025967-78-5
BIRT 377
213211-10-0
A 286982
280749-17-9
509083-77-6
BMS587101
509083-77-6

Background


An overview of LFA-1

The lymphocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 orαLβ2, is an integrin molecule in the human body, which plays a major role in regulating T cell activation and migration. LFA-1 distributes widely on hematopoietic cells, where it mediates intercellular interactions within the immune system and between leukocytes and non-blood cells. Several intercellular adhesion molecules (ICAMs), such as ICAM-1 and junctional adhesion molecule 1, are common ligands for LFA-1. LFA-1 consists of the αL andβ2 variants of integrin chains. Like other integrins with an I-domain containing αchain, ligand binding is localized to this domain.

Inhibition of LFA-1

There are two known classes of LFA-1 small molecular weight inhibitors: one is a group of allosteric inhibitors known to interact with a hydrophobic cleft between the α7-helix and the central β-sheet, which is known as the ‘I-domain allosteric site’ or IDAS. There is a wide range of structurally distinct families of small molecules known to inhibit the LFA-1/ICAM-1 interaction in this way, such as the statins (lovastatin, simvastatin, LFA878 and LFA703 etc.), cinnamides (IC487475), and hydantoins (BIRT-377). In addition, there are ICAM-1 derived peptides (cIBR and cIBC) that function similarly to small molecule allosteric inhibitors. The second group is known as the α/β I-like inhibitors(XVA143).

LFA-1 and diseases

The LFA-1/ICAM-1 interaction is indispensable in the adhesion of lymphocytes to the vascular endothelium and their subsequent extravasation into the surrounding tissue, which is a part of normal immune function and is thought to play a role in the pathogenesis of inflammatory diseases such as psoriasis, rheumatoid arthritis, and transplant rejection. Besides, LFA-1 plays an integral role in the mechanisms of cancer cell adhesion and metastasis, and has been implicated in a variety of cancers such as melanoma, gastrointestinal carcinoma and lymphoma. Involvement in inflammatory diseases and cancer makes LFA-1 a potential therapeutic target for inhibitors designed to disrupt the ICAM-1/LFA-1 interaction.

References:

1. Manuel Reina, Enric Espel. Role of LFA-1 and ICAM-1 in Cancer. Cancers, 2017, 9(11):153. Brandon L. Walling and Minsoo Kim. LFA-1 in T Cell Migration and Differentiation. Frontiers in immunology, 2018, 9: 952.

2.Tahl Zimmerman, Francisco J. Blanco. Inhibitors Targeting the LFA-1/ICAM-1 Cell-Adhesion Interaction: Design and Mechanism of Action. Current Pharmaceutical Design, 2008, 14(22): 2128-2139.