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Generation of an LFA-1 Antagonist by the Transfer of the ICAM-1 Immunoregulatory Epitope to a Small Molecule

2002; American Association for the Advancement of Science; Volume: 295; Issue: 5557 Linguagem: Inglês

10.1126/science.295.5557.1086

1095-9203

Thomas R. Gadek, Daniel J. Burdick, Robert S. McDowell, Mark Stanley, James C. Marsters, K. J. Paris, D. A. OARE, Mark Reynolds, C. Ladner, Kimberly Zioncheck, W. P. Lee, Peter Gribling, Mark S. Dennis, Nicholas J. Skelton, Daniel B. Tumas, Kevin Clark, Susan M. Keating, Maureen H. Beresini, Jefferson Tilley, Leonard G. Presta, Sarah Bodary,

Immunotherapy and Immune Responses

The protein-protein interaction between leukocyte functional antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is critical to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its association with LFA-1, to a small-molecule framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-molecule mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.