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Inhibition of Endotoxin Response by E5564, a Novel Toll-Like Receptor 4-Directed Endotoxin Antagonist
- Source :
- Journal of Pharmacology and Experimental Therapeutics. 304:1093-1102
- Publication Year :
- 2002
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2002.
-
Abstract
- Alpha-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-beta-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-alpha 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 microM. E5564 blocked LPS-mediated activation of nuclear factor-kappaB 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]-beta-O-phosphono-alpha-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.
- Subjects :
- Lipopolysaccharides
Male
Time Factors
Lipopolysaccharide
medicine.medical_treatment
Guinea Pigs
Receptors, Cell Surface
Pharmacology
Biology
Monocytes
Rats, Sprague-Dawley
Mice
chemistry.chemical_compound
In vivo
Cell surface receptor
Escherichia coli
medicine
Animals
Drosophila Proteins
Humans
Drug Interactions
Receptor
Cells, Cultured
Toll-like receptor
Membrane Glycoproteins
Tumor Necrosis Factor-alpha
Macrophages
Toll-Like Receptors
Shock, Septic
Rats
Endotoxins
Mice, Inbred C57BL
Toll-Like Receptor 4
Disease Models, Animal
Blood
Lipid A
Cytokine
Biochemistry
chemistry
Cell culture
Cytokines
Molecular Medicine
Tumor necrosis factor alpha
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 304
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....3c3e6c351af996936ca8c0e87b66746d