Generation of an LFA-1 Antagonist by the Transfer of the ICAM-1 Immunoregulatory Epitope to a Small Molecule
- 8 February 2002
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 295 (5557), 1086-1089
- https://doi.org/10.1126/science.295.5557.1086
Abstract
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.Keywords
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