title: Biological activity of synthetic phosphonooxyethyl analogs of lipid A and lipid A partial structures.
abstract: We investigated the biological activity of four new synthetic analogs of lipid A, termed PE-1, PE-2, PE-3, and PE-4. All compounds contain an alpha-oxyethyl-linked (-O-CH2-CH2-) phosphoryl group in position 1 of the reducing glucosaminyl residue (GlcN I) of lipid A. PE-1 is a hexaacylated analog of Escherichia coli lipid A (compound 506). PE-2 differs from PE-1 in carrying two myristic acid residues at GlcN I. PE-3 has the same acylation pattern as PE-2, but GlcN I is present in the beta anomeric form. Finally, PE-4 represents an analog of tetraacyl precursor Ia (compound 406). Structure-activity relationships of these compounds were determined by measuring their capacity to induce tumor necrosis factor alpha, interleukin 1, and interleukin 6 release by human mononuclear cells and to cause mitogenicity of murine spleen cells. The results show that replacement of the glycosidic phosphoryl residue by a phosphonooxyethyl group had no substantial effect on the biological activity of compounds. However, the anomeric configuration of GlcN I was found to be of great biological relevance, as, in general, the alpha anomer (PE-2) expressed high activity, and the beta anomer (PE-3) expressed low mediator-inducing and mitogenic activity. The absence of the 3-hydroxyl groups within the acyl residues at GlcN I in PE-2 was found to only slightly affect the induction of monokines in human mononuclear cells compared with that of PE-1 or lipid A (506). These stable 1-phosphonooxyethyl analogs of lipid A may be candidates in the development of immunomodulators for the treatment of systemic endotoxicosis.
authors.affiliation: Department of Immunology and Cell Biology, Forschungsinstitut Borstel, Germany.
authors.forename: A J
authors.initials: AJ
authors.lastname: Ulmer
authors.forename: H
authors.initials: H
authors.lastname: Heine
authors.forename: W
authors.initials: W
authors.lastname: Feist
authors.forename: S
authors.initials: S
authors.lastname: Kusumoto
authors.forename: T
authors.initials: T
authors.lastname: Kusama
authors.forename: H
authors.initials: H
authors.lastname: Brade
authors.forename: U
authors.initials: U
authors.lastname: Schade
authors.forename: E T
authors.initials: ET
authors.lastname: Rietschel
authors.forename: H D
authors.initials: HD
authors.lastname: Flad
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008050:Lipid A / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D011749:Pyrogens / Q000494:pharmacology; D011817:Rabbits; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D008050:Lipid A; D011749:Pyrogens; D014409:Tumor Necrosis Factor-alpha