lipid-a and eritoran

Lipopolysaccharide (LPS), an endotoxin of Gram-negative bacteria, activates the innate immunity system through a receptor complex of myeloid differentiation 2 (MD-2) and toll-like receptor 4 (TLR4). MD-2 directly recognizes the lipid A domain of LPS, which triggers MD-2/TLR4-mediated cellular response aimed at eliminating the invaded pathogen. However, excess production of inflammatory mediators is harmful to host tissue and this can cause septic death in extreme cases. MD-2 represents an attractive therapeutic target of inflammatory and immune diseases in human. In particular, eritoran is a synthetic tetraacylated lipid A that binds directly to MD-2 and antagonizes LPS binding to the same site, and it ameliorates various inflammatory conditions due to infection or sterile organ injury. In this review, we outline the recent advances in the structure biology of ligand interaction with MD-2/TLR4, and highlight the MD-2-directed LPS antagonists, which are natural and synthetic chemicals, under development to treat inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Disaccharides; Glycolipids; Humans; Inflammation; Lipid A; Lipopolysaccharides; Lymphocyte Antigen 96; Sugar Phosphates; Toll-Like Receptor 4

Eritoran, a synthetic analogue of lipid A, has been shown to bind to TLR4/MD-2 complex and thereby block the interaction of endotoxins with TLR4. We report here the results of a study conducted to assess the single-dose safety and tolerability, as well as the pharmacokinetics and pharmacodynamics, of eritoran infusion in Japanese and Caucasian healthy adult men. Sixty-four men (aged 20-45 years; body mass index 18-30 kg/m(2)) were randomized into four groups: 4-mg total dose (six Japanese and six Caucasian men); 12-mg total dose (12 Japanese and 12 Caucasian men); 28-mg total dose (six Japanese and six Caucasian men); and placebo (eight Japanese and eight Caucasian men). Eritoran in single doses up to 28 mg over 4 h was well tolerated, with no apparent ethnic differences noted. Plasma concentrations were slightly higher in Japanese versus Caucasian men; these differences were not significant after adjustment for differences in body mass (clearance: approximately 1.2 ml/h/kg; volume of distribution at steady state: approximately 0.07 l/kg). The ex vivo endotoxin inhibitory activity of eritoran was similar in Japanese and Caucasian men. The data do not indicate any need for clinical dose adjustment for possible ethnic-based differences in drug distribution or metabolism.

Topics: Adult; Asian People; Disaccharides; Endotoxins; Humans; Infusions, Intravenous; Japan; Lipid A; Male; Middle Aged; Protein Binding; Sugar Phosphates; Toll-Like Receptor 4; White People; Young Adult

Autophagy, an ancient homeostasis mechanism for macromolecule degradation, performs an important role in host defense by facilitating pathogen elimination. To counteract this host defense strategy, bacterial pathogens have evolved a variety of mechanisms to avoid or otherwise dysregulate autophagy by phagocytic cells so as to enhance their survival during infection. Neisseria gonorrhoeae is a strictly human pathogen that causes the sexually transmitted infection, gonorrhea. Phosphoethanolamine (PEA) addition to the 4' position of the lipid A (PEA-lipid A) moiety of the lipooligosaccharide (LOS) produced by gonococci performs a critical role in this pathogen's ability to evade innate defenses by conferring decreased susceptibility to cationic antimicrobial (or host-defense) peptides, complement-mediated killing by human serum and intraleukocytic killing by human neutrophils compared to strains lacking this PEA decoration. Heretofore, however, it was not known if gonococci can evade autophagy and if so, whether PEA-lipid A contributes to this ability. Accordingly, by using murine macrophages and human macrophage-like phagocytic cell lines we investigated if PEA decoration of gonococcal lipid A modulates autophagy formation. We report that infection with PEA-lipid A-producing gonococci significantly reduced autophagy flux in murine and human macrophages and enhanced gonococcal survival during their association with macrophages compared to a PEA-deficient lipid A mutant. Our results provide further evidence that PEA-lipid A produced by gonococci is a critical component in the ability of this human pathogen to evade host defenses.

Topics: Animals; Autophagy; Cell Line; Chemokines; Disaccharides; Ethanolamines; Host-Pathogen Interactions; Humans; Lipid A; Macrophages; Mice; Neisseria gonorrhoeae; Phagosomes; Sugar Phosphates

Lipid A, the active moiety of LPS, exerts its effects through interaction with TLR4, triggering a signalling cascade that results in the release of pro-inflammatory cytokines. Eritoran is a lipid A analogue that competes with LPS for binding to TLR4; however, after intravenous administration, it undergoes a time-dependent deactivation as a consequence of binding to high-density lipoproteins (HDLs). The site of eritoran association with HDL remains unknown. Therefore the aim of this study was to determine if HDL-associated apolipoproteins A1, A2, serum amyloid A (SAA) and C1, inhibit the ability of eritoran to block LPS-induced TNF-α release from whole blood. Eritoran activity after LPS stimulation in human whole blood was assessed in the presence of reconstituted HDL (rHDL) containing different apos. In rHDL, the major apolipoproteins in both the healthy and septic state, A1 and SAA, caused a significant reduction in eritoran antagonistic activity and had a greater effect than minor apolipoproteins A2 and C1. Apolipoproteins associated with HDL are likely to facilitate eritoran deactivation. Apolipoproteins A1 and SAA should be of particular focus as they are the major apos found on HDL in both the healthy and septic state. Further evaluation of the physical association between apolipoproteins and eritoran should be explored.

Topics: Apolipoprotein A-I; Apolipoprotein A-II; Binding, Competitive; Blood Cells; Disaccharides; Humans; Lipid A; Lipoproteins, HDL; Molecular Structure; Serum Amyloid A Protein; Sugar Phosphates; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha