title: Endotoxic properties of chemically synthesized lipid A part structures. Comparison of synthetic lipid A precursor and synthetic analogues with biosynthetic lipid A precursor and free lipid A.
abstract: Synthetic lipid A part structures corresponding structurally to a biosynthetic lipid A disaccharide precursor have been analyzed for endotoxic activity in several systems in vivo and in vitro. It was found that a synthetic beta-1,6-linked D-glucosamine disaccharide, which carries four molar equivalents of (R)-3-hydroxytetradecanoyl residues in positions 2, 3, 2' and 3' and phosphoryl groups in positions 1 and 4' (preparation 406), exhibited lethal toxicity, B lymphocyte mitogenicity, the capacity to engender prostaglandin formation in macrophages and to induce endotoxic tolerance, as well as serological lipid A antigenicity. On a weight basis, preparation 406 was of comparable activity to lipid A precursor and bacterial free lipid A. Preparation 406, like lipid A precursor, lacked, however, the ability to induce the local Shwartzman phenomenon and both preparations were of moderate pyrogenicity. Two further synthetic analogues which contained only one phosphoryl group (preparation 404 at C-4', preparation 405 at C-1) showed comparable or diminished activity depending on the test system employed, except in the capacity to inactivate complement where they exhibited, in contrast to preparation 406, significant activity. The results show that the endotoxic principle of lipopolysaccharides, as postulated previously is embedded in the lipid A component. Our results also suggest initial conclusions on the structural requirements for the expression of endotoxin activities.
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial; D003169:Complement Inactivator Proteins; D004731:Endotoxins; D005260:Female; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008050:Lipid A / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens; D008938:Mitosis / Q000187:drug effects; D011453:Prostaglandins / Q000096:biosynthesis; D011749:Pyrogens; D012882:Skin Tests
chemical_list: D000942:Antigens, Bacterial; D003169:Complement Inactivator Proteins; D004731:Endotoxins; D008050:Lipid A; D008934:Mitogens; D011453:Prostaglandins; D011749:Pyrogens