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Vol. 304, Issue 3, 1093-1102, March 2003
Biology Section (M.M., J.R.R., J.B., S.K., M.P., J.C., F.G.) and
Chemistry Section (W.J.C.), Eisai Research Institute of Boston, Inc.,
Andover, Massachusetts; and Tsukuba Research Laboratories (T.K., A.K.),
Eisai Co. Ltd., Tsukuba, Japan
-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-
-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- 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-
B
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]--O-phosphono--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.
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