The search for effective small molecule inhibitors of protein-protein interactions is a major goal in pharmaceutical research. Gadek et al. describe the design of a small molecule that mimics an epitope of the ligand of the integrin LFA-1. The lead compound (ortho-bromobenzoyl tryptophan), originally identified as inhibiting LFA-1, was optimized by using information gained from the separate evolution of a noncontinuous peptide epitope of intercellular cell-adhesion molecule I-CAM-1. The final result of the modifications led to a compound that retained characteristics of the small molecule and bound LFA with high affinity. The compound also effectively blocked lymphocyte proliferation and contact hypersensitivity in mice.
T. R. Gadek, D. J. Burdick, R. S. McDowell, M. S. Stanley, J. C. Marsters Jr., 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, and S. C. Bodary, Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science 295, 1086-1089 (2002). [Abstract] [Full Text]