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

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Science  08 Feb 2002:
Vol. 295, Issue 5557, pp. 1086-1089
DOI: 10.1126/science.295.5557.1086

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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.

  • * To whom correspondence should be addressed. E-mail: trg{at} (T.R.G.); burdick.dan{at} (D.J.B.)

  • Present address: Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

  • Present address: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.

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