Inhibition of Endotoxin Response by E5564, a Novel Toll-Like Receptor 4-Directed Endotoxin Antagonist
- 25 November 2002
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 304 (3), 1093-1102
- https://doi.org/10.1124/jpet.102.044487
Abstract
α-d-Glucopyranose,3-O-decyl-2-deoxy-6-O-[2-deoxy-3-O-[(3R)-3-methoxydecyl]-6-O-methyl-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-4-O-phosphono-β-d-glucopyranosyl]-2-[(1,3-dioxotetradecyl)amino]-1-(dihydrogen phosphate), tetrasodium salt (E5564) is a second-generation synthetic lipodisaccharide designed to antagonize the toxic effects of endotoxin, a major immunostimulatory component of the outer cell membrane of Gram negative bacteria. In vitro, E5564 dose dependently (nanomolar concentrations) inhibited lipopolysaccharide (LPS)-mediated activation of primary cultures of human myeloid cells and mouse tissue culture macrophage cell lines as well as human or animal whole blood as measured by production of tumor necrosis factor-α and other cytokines. E5564 also blocked the ability of Gram negative bacteria to stimulate human cytokine production in whole blood. In vivo, E5564 blocked induction of LPS-induced cytokines and LPS or bacterial-induced lethality in primed mice. E5564 was devoid of agonistic activity when tested both in vitro and in vivo and has no antagonistic activity against Gram positive-mediated cellular activation at concentrations up to 1 μM. E5564 blocked LPS-mediated activation of nuclear factor-κB in toll-like receptor 4/MD-2-transfected cells. In a mouse macrophage cell line, activity of E5564 was independent of serum, suggesting that E5564 exerts its activity through the cell surface receptor(s) for LPS, without the need for serum LPS transfer proteins. Similar to (6-O-{2-deoxy-6-O-methyl-4-O-phosphono-3-O-[(R)-3-Z-dodec-5-endoyloxydecl]-2-[3-oxo-tetradecanoylamino]-β-O-phosphono-α-d-glucopyranose tetrasodium salt (E5531), another lipid A-like antagonist, E5564 associates with plasma lipoproteins, causing low concentrations of E5564 to be quantitatively inactivated in a dose- and time-dependent manner. However, compared with E5531, E5564 is a more potent inhibitor of cytokine generation, and higher doses retain activity for durations likely sufficient to permit clinical application. These results indicate that E5564 is a potent antagonist of LPS and lacks agonistic activity in human and animal model systems, making it a potentially effective therapeutic agent for treatment of disease states caused by endotoxin.Keywords
This publication has 33 references indexed in Scilit:
- Blocking of Responses to Endotoxin by E5564 in Healthy Volunteers with Experimental EndotoxemiaThe Journal of Infectious Diseases, 2003
- LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantationJCI Insight, 2001
- Human models of innate immunity: local and systemic inflammatory responsesInnate Immunity, 2001
- LPS-binding protein circulates in association with apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interactionJCI Insight, 2001
- Cellular Events Mediated by Lipopolysaccharide-stimulated Toll-like Receptor 4Published by Elsevier BV ,2000
- Consequences of Interaction of a Lipophilic Endotoxin Antagonist with Plasma LipoproteinsAntimicrobial Agents and Chemotherapy, 2000
- Significance of systemic endotoxaemia in inflammatory bowel disease.Gut, 1995
- Receptor-Dependent Mechanisms of Cell Stimulation by Bacterial EndotoxinAnnual Review of Immunology, 1995
- Endotoxemia after major vascular operationsJournal of Vascular Surgery, 1993
- Synthetic and natural Escherichia coli free lipid A express identical endotoxic activitiesEuropean Journal of Biochemistry, 1985