title: The generalized endotoxic principle.
abstract: Bacterial lipopolysaccharides (endotoxins, LPS) belong to the most potent immunostimulators in mammals. The endotoxic principle of LPS is located in its lipid A moiety, which for Escherichia coli-type LPS consists of a hexaacylated diphosphoryl diglucosamine backbone. This lipid A adopts a cubic inverted aggregate structure from which a conical shape of the molecule can be deduced, whereas the tetraacyl lipid A precursor IVa adopts a cylindrical shape and is endotoxically inactive, but antagonizes active LPS. We hypothesize that non-lipid A amphiphiles with similar physicochemical properties of amphiphilicity, charge, and shape, might mimic the respective lipid A. To test this hypothesis, phospholipid-like amphiphiles with six acyl chains attached to a bisphosphorylated serine-like backbone of varying length replacing the diglucosamine backbone were synthesized. The compound with a short backbone fulfills all criteria of an endotoxic agonist, and that with long backbone fulfills those of an antagonist. This holds true for the human as well as for the murine system. Interestingly, these compounds are inactive in the Limulus amebocyte lysate test which is specific for LPS diglucosamine backbone. These results define a general endotoxic principle and, furthermore, provide new insights into an understanding of early steps of endotoxin action.
authors.affiliation: Forschungszentrum Borstel, Germany. useydel@fz-borstel.de
authors.forename: Ulrich
authors.initials: U
authors.lastname: Seydel
authors.forename: Lynn
authors.initials: L
authors.lastname: Hawkins
authors.forename: Andra B
authors.initials: AB
authors.lastname: Schromm
authors.forename: Holger
authors.initials: H
authors.lastname: Heine
authors.forename: Olaf
authors.initials: O
authors.lastname: Scheel
authors.forename: Michel H J
authors.initials: MH
authors.lastname: Koch
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D004731:Endotoxins / Q000737:chemistry* / Q000276:immunology; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008033:Limulus Test; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008081:Liposomes; D008213:Lymphocyte Activation; D008262:Macrophage Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D010743:Phospholipids / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000502:physiology; D013329:Structure-Activity Relationship; D051193:Toll-Like Receptors; D014961:X-Ray Diffraction
chemical_list: C475978:ER 803022; C475979:ER 805046; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D008081:Liposomes; D008562:Membrane Glycoproteins; D010743:Phospholipids; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors