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.
MeSH terms
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Amino Acid Sequence
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / metabolism
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Cyclosporine / pharmacology
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Dermatitis, Irritant / drug therapy
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Dinitrofluorobenzene
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Drug Design
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Enzyme-Linked Immunosorbent Assay
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Epitopes
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Female
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Humans
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Immunoglobulin Fab Fragments / immunology
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Immunoglobulin Fab Fragments / pharmacology
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Immunosuppressive Agents / chemical synthesis
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Immunosuppressive Agents / chemistry
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Immunosuppressive Agents / metabolism
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Immunosuppressive Agents / pharmacology*
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Intercellular Adhesion Molecule-1 / chemistry
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Intercellular Adhesion Molecule-1 / immunology*
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Intercellular Adhesion Molecule-1 / metabolism*
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Lymphocyte Culture Test, Mixed
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Lymphocyte Function-Associated Antigen-1 / immunology
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Lymphocyte Function-Associated Antigen-1 / metabolism*
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Mice
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Mice, Inbred BALB C
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Molecular Mimicry
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Mutagenesis
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Protein Structure, Secondary
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Structure-Activity Relationship
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Thiophenes / chemical synthesis*
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Thiophenes / chemistry
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Thiophenes / metabolism
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Thiophenes / pharmacology*
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beta-Alanine / analogs & derivatives
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beta-Alanine / chemical synthesis*
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beta-Alanine / chemistry
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beta-Alanine / metabolism
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beta-Alanine / pharmacology*
Substances
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2-(4-(3-hydroxy-3-(hydroxyphenyl)propyl)-2,6-dichlorophenyl)carbomylamino-3-((thiophen-2-yl)carbonylamino)propanoic acid
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Anti-Inflammatory Agents, Non-Steroidal
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Epitopes
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Immunoglobulin Fab Fragments
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Immunosuppressive Agents
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Lymphocyte Function-Associated Antigen-1
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Thiophenes
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beta-Alanine
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Intercellular Adhesion Molecule-1
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Cyclosporine
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Dinitrofluorobenzene