| Literature DB >> 11834839 |
T R Gadek1, D J Burdick, R S McDowell, M S Stanley, J C Marsters, K J Paris, D A Oare, M E Reynolds, C Ladner, K A Zioncheck, W P Lee, P Gribling, M S Dennis, N J Skelton, D B Tumas, K R Clark, S M Keating, M H Beresini, J W Tilley, L G Presta, S C Bodary.
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.Entities:
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Year: 2002 PMID： 11834839 DOI： 10.1126/science.295.5557.1086
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728