Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule |
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| Authors: | Gadek T R Burdick D J McDowell R S Stanley M S Marsters J C Paris K J Oare D A Reynolds M E Ladner C Zioncheck K A Lee W P Gribling P Dennis M S Skelton N J Tumas D B Clark K R Keating S M Beresini M H Tilley J W Presta L G Bodary S C |
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| Institution: | Department of Bioorganic Chemistry, Genentech, One DNA Way, South San Francisco, CA 94080, USA. trg@gene.com |
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| 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. |
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