TAILIEUCHUNG - Báo cáo khoa học: Physicochemical characterization of carboxymethyl lipid A derivatives in relation to biological activity

Lipopolysaccharide (LPS) from the outer membrane of Gram-negative bac-teria belongs to the most potent activators of the mammalian immune sys-tem. Its lipid moiety, lipid A, the ‘endotoxic principle’ of LPS, carries two negatively charged phosphate groups and six acyl chain residues in a defined asymmetric distribution (corresponding to synthetic compound 506). Tetraacyl lipid A (precursor IVa or synthetic 406), which lacks the two hydroxylated acyl chains, is agonistically completely inactive, but is a strong antagonist to bioactive LPS when administered to the cells before LPS addition. . | ềFEBS Journal Physicochemical characterization of carboxymethyl lipid A derivatives in relation to biological activity Ulrich Seydel1 Andra B. Schromm1 Lore Brade1 Sabine Gronow1 Jorg Andra1 Mareike Muller1 Michel H. J. Koch2 Koichi Fukase3 Mikayo Kataoka3 Masaya Hashimoto3 Shoichi Kusumoto3 and Klaus Brandenburg1 1 Forschungszentrum Borstel Leibniz-Zentrum fur Medizin und Biowissenschaften Borstel Germany 2 European Molecular Biology Laboratory c o DESY Hamburg Germany 3 Osaka University Department of Chemistry Osaka Japan Keywords endotoxic shock inflammation lipopolysaccharide signal transduction Correspondence U. Seydel Forschungszentrum Borstel Division of Biophysics Parkallee 10 D-23845 Borstel Germany Fax 49 4537 188632 Tel 49 4537 188232 E-mail useydel@ Received 6 September 2004 revised 3 November 2004 accepted 5 November 2004 doi Lipopolysaccharide LPS from the outer membrane of Gram-negative bacteria belongs to the most potent activators of the mammalian immune system. Its lipid moiety lipid A the endotoxic principle of LPS carries two negatively charged phosphate groups and six acyl chain residues in a defined asymmetric distribution corresponding to synthetic compound 506 . Tetraacyl lipid A precursor IVa or synthetic 406 which lacks the two hydroxylated acyl chains is agonistically completely inactive but is a strong antagonist to bioactive LPS when administered to the cells before LPS addition. The two negative charges of lipid A represented by the two phosphate groups are essential for agonistic as well as for antagonistic activity and no highly active lipid A are known with negative charges other than phosphate groups. We hypothesized that the phosphate groups could be substituted by other negatively charged groups without changing the endotoxic properties of lipid A. To test this hypothesis we synthesized carboxymethyl CM derivatives of hexaacyl lipid A CM-506 and Bis-CM-506 and of tetraacyl lipid A .

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