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Science 295 (5557): 1086-1089

Copyright © 2002 by the American Association for the Advancement of Science

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

T. R. Gadek,* D. J. Burdick,* R. S. McDowell,dagger M. S. Stanley, J. C. Marsters Jr., K. J. Paris, D. A. Oare,ddagger 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

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.

Departments of 1Bioorganic Chemistry, 2Immunology, 3Protein Engineering, 4Pathology, 5Small Molecule Pharmacology, and 7Antibody Technology, Genentech, One DNA Way, South San Francisco, CA 94080, USA. 6Roche Research Center, Hoffmann-La Roche, Nutley, NJ 07110, USA.
*   To whom correspondence should be addressed. E-mail: trg{at}gene.com (T.R.G.); burdick.dan{at}gene.com (D.J.B.)

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

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



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