We have proposed a model of activation of receptor complex TLR4/MD-2 by endotoxin (LPS): Hydrophobic residues at positions 82, 85 and 87 of MD-2 are essential both for transfer of LPS from CD14 to monomeric MD-2 and for TLR4 activation. Phe-440 and Phe-463, conserved hydrophobic residues of the TLR4 ectodomain, are essential for activation of TLR4 by LPS. Val-82, Met-85 and Leu-87 in MD-2 and distal portions of a secondary acyl chain of hexaacylated lipid A form a hydrophobic surface that interacts with Phe-440 and Phe-463 on a neighboring TLR4/MD-2/LPS complex, driving TLR4 activation.
COBISS.SI-ID: 4120602
MD-2 is a part of the TLR4 signaling complex with indispensable role in activation of the LPS signaling pathway and thus a suitable target for the therapeutic inhibition of TLR4 signaling. Compounds with affinity for the hydrophobic pocket in MD-2 were tested. IAANS and N-pyrene maleimide formed covalent bond with MD-2 through Cys133 and inhibited LPS signaling. Cell activation was inhibited by JTT-705 originally targeted against cholesterol-ester transfer protein and antirheumatic compound auranofin. Oral intake of JTT-705 significantly inhibited LPS-triggered TNFa production in mice.
COBISS.SI-ID: 4173082