Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule
| Autor: | Kenneth J. Paris, M. S. Stanley, M. H. Beresini, D. B. Tumas, W. P. Lee, N. J. Skelton, M. E. Reynolds, Kevin R Clark, J. C. Marsters, M. S. Dennis, J. W. Tilley, L. G. Presta, D. J. Burdick, D. A. Oare, P. Gribling, T. R. Gadek, C. Ladner, K. A. Zioncheck, S. C. Bodary, S. M. Keating, R. S. McDowell |
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| Rok vydání: | 2002 |
| Předmět: |
Lymphocyte
chemical and pharmacologic phenomena Enzyme-Linked Immunosorbent Assay Thiophenes Biology Epitope Protein Structure Secondary Epitopes Immunoglobulin Fab Fragments Mice Structure-Activity Relationship Immune system In vivo medicine Animals Humans Amino Acid Sequence ICAM-1 Mice Inbred BALB C Multidisciplinary Anti-Inflammatory Agents Non-Steroidal Molecular Mimicry hemic and immune systems Mixed lymphocyte reaction Intercellular Adhesion Molecule-1 Molecular biology Small molecule Lymphocyte Function-Associated Antigen-1 Cell biology medicine.anatomical_structure Mutagenesis Drug Design biology.protein Cyclosporine beta-Alanine Dermatitis Irritant Dinitrofluorobenzene Female Antibody Lymphocyte Culture Test Mixed Immunosuppressive Agents |
| Zdroj: | Science (New York, N.Y.). 295(5557) |
| ISSN: | 1095-9203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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