| Title | Free thiol group of MD-2 as the target for inhibition of the LPS-induced cell activation. | | Author(s) | Manèek Keber M, Gradisar H, Iñigo Pestaña M, de Tejada GM, Jerala R | | Institution | Natl. ins. chem., Slovenia; | | Source | J Biol Chem 2009 May 27. | | Abstract | MD-2 is a part of the Toll-like 4 signaling complex with indispensable role in activation of the LPS signaling pathway and thus a suitable target for the therapeutic inhibition of TLR4 signaling. Elucidation of MD-2 structure provides foundation for rational design of inhibitors which 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 free cysteine residue of MD-2 were tested. Fluorescent compounds 2-(4'-(iodoacetamido)anilino) naphthalene-6-sulfonic acid and N-pyrene maleimide formed covalent bond with MD-2 through Cys133 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 TNFa production in mice. Thiol group of MD-2 also represents the target of environmental or endogenous thiol-reactive compounds that are produced in inflammation. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19473973 |
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