LFA-1 lymphocyte function-associated antigen

Marlin, S. D. and Springer, T. A. (1987). Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell 51, 813-819. 

The quaternization method is also highlighted by the short asymmetric synthesis of cell adhesion molecule BIRT-377 (Scheme 5.24), which is a potent inhibitor of the interaction between intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) [16]. Thus, asymmetricp-bromobenzylation of the alanine derivative 42 (R1 = Me) with (S)-18 under similar phase-transfer conditions as described above gave rise to p-bromobenzylalanine ester 10 in 97% ee (83% yield). A similar asymmetric p-bromobenzylation of alanine ethyl ester 42 (R1 = Me, R= Et) gave the amino ester 47 (R= Et) in 90% ee (86% yield). The amino ester 47 (R = t-Bu or Et) was treated with 3,5-dichlorophenyl isocyanate in the presence of sodium carbonate in dimethylsulfoxide (DMSO) to furnish the hydantoin 48 in 86%... 

BIRT-377 (1), a small molecule inhibitor of lymphocyte function-associated antigen 1 (LFA-1), was first discovered by Kelly and coworkers in 1999. It was shown to have potential therapeutic utility in the treatment of a variety of inflammatory and immune disorders. In binding to intercellular adhesion molecules, the cell-surface receptor LFA-1 allows many cell-cell adhesion events that control immunological functions. A lack of these synaptic functions leads to potentially life-threatening immunodeficiency diseases. In case of overactive immune responses, an LFA-1 inhibitor can be used to attenuate the inflammatory responses. These immunosuppressive activities have been tested in vitro, and early clinical trials on transplantation have already been undertaken. ... 

Due to their inhibitory effects on DNA methylation, procainamide and hydralazine can induce autoreactive T cells by upregulating the expression of lymphocyte function-associated antigen-1 (LFA-1), which causes the cells to proliferate in response to normally subthreshold stimuli, including self (Yung et al. 1995). As a result, the adoptive transfer of T cells modified by in vitro treatment with procainamide or hydralazine induces an autoimmune disorder characterized by antinuclear antibodies (ANAs) and immune complex glomerulonephritis in naive mice (Quddus et al. 1993). 

In the following, two LEVS case studies wall be discussed in greater detail the identification of (1) an attractive antagonist of the lymphocyte function-associated antigen-1 (LFA-l) [42] and (2) target-selective inhibitors for cathepsin K (CatK) [43]. 

Expression of several adhesion molecules increases in an age-dependent manner. The adhesion and activation of immune cells mediate inflammation. Soda et al. established that lymphocyte function-associated antigen-1 (LFA-1) is an adhesion molecule and demonstrated that spermidine suppresses LFA-1 expression (Soda... 

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