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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Gradisar, Helena Iñigo Pestaña, Melania Jerala, Roman Mancek-keber, Mateja Martinez De Tejada, Guillermo |
| Description | Author Affiliation: Mancek-Keber M ( Department of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.) |
| Abstract | MD-2 is a part of the Toll-like 4 signaling complex with an indispensable role in activation of the lipopolysaccharide (LPS) signaling pathway and thus a suitable target for the therapeutic inhibition of TLR4 signaling. Elucidation of MD-2 structure provides a foundation for rational design of inhibitors that bind to MD-2 and inhibit LPS signaling. Since the hydrophobic binding pocket of MD-2 provides little specificity for inhibitors, we have investigated targeting the solvent-accessible cysteine residue within the hydrophobic binding pocket of MD-2. Compounds with affinity for the hydrophobic pocket that contain a thiol-reactive group, which mediates covalent bond formation with the free cysteine residue of MD-2, were tested. Fluorescent compounds 2-(4'-(iodoacetamido)anilino)naphthalene-6-sulfonic acid and N-pyrene maleimide formed a covalent bond with MD-2 through Cys(133) and inhibited LPS signaling. Cell activation was also inhibited by thiol-reactive compounds JTT-705 originally targeted against cholesterol ester transfer protein and antirheumatic compound auranofin. Oral intake of JTT-705 significantly inhibited endotoxin-triggered tumor necrosis factor alpha production in mice. The thiol group of MD-2 also represents the target of environmental or endogenous thiol-reactive compounds that are produced in inflammation. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 29 |
| Volume Number | 284 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2009-07-17 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Lipopolysaccharides Pharmacology Lymphocyte Antigen 96 Metabolism Signal Transduction Drug Effects Toll-Like Receptors Animals Auranofin Chemistry Binding Sites Cell Line Cysteine Dose-Response Relationship, Drug Maleimides Mice Mice, Inbred C57BL Models, Molecular Molecular Structure Protein Binding Protein Structure, Tertiary Pyrenes Sulfhydryl Compounds Tumor Necrosis Factor-alpha Blood Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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