Bacterial cell wall components such as LPS can activate the host innate immune response by activation of the Toll-like receptor (TLR) family of pathogen recognition molecules,
13 which therefore represent a potential target for immune intervention. TLR4 is the most complex and sensitive member of this receptor family, an accessory molecules lipid A binding protein, CD14 and MD-2 to detect picomolar levels of the lipid A moiety LPS,
14 and is the only member of the TLR family that activates both the MyD88 and the TRIF intracellular signaling pathways.
15 Antagonistic rather than agonistic lipid A activity on TLR4, was initially demonstrated for
Rhodobacter sphaeroides lipid A (RSLA), which has five acyl chains compared with six chains on lipid A from most Gram-negative bacteria. RSLA also has pronounced antagonistic activity for LPS Gram-negative bacteria, and has only minor agonist activity on some cell types.
16 17 18 The structure of RSLA has therefore provided the basis for generating synthetic lipid A antagonists,
19 one of which is eritoran tetrasodium. This compound, which has four acyl chains, inhibits LPS-induced monocyte activation, LPS endotoxemia, and LPS-induced chronic airway disease and is undergoing clinical trials for bacterial sepsis.
20 21 22 Furthermore, the compound has successfully undergone phase I clinical trials and was shown to be safe and nontoxic in normal volunteers.
23 24 25 Recent analysis of the crystal structure of TLR4 shows that eritoran tetrasodium binds to the MD-2 accessory molecule associated with TLR4
26 and is consistent with the mode of action being directly antagonistic to lipid A binding, as the tetra-acylated eritoran tetrasodium does not initiate TLR4 dimerization or activation of the signaling cascade.
19 26