title: Antiendotoxin activity of lipid A analogues: requirements of the chemical structure.
abstract: Lipid X, a monosaccharide precursor of lipid A, has been found to prevent death in animals given a lethal dose of endotoxin, but the mechanism of this protective effect is unknown. We previously reported that lipid X blocks endotoxin-induced priming of human neutrophils in a manner consistent with competitive inhibition. To determine the molecular requirements for this antiendotoxin activity, we studied several derivatives of lipid X using the neutrophil priming assay. Neutrophil priming was quantitated by measuring stimulated superoxide (O2-) release. The removal of either acyl group from lipid X or even the simple change of the amide to an ester linkage at C2 of the glucosamide ring resulted in a marked loss of antagonism. Monosaccharide analogues, structurally related to native lipid A by the presence of acyloxyacyl side chains, demonstrated marked inhibition of endotoxin-induced priming at low concentrations but an endotoxin-like, priming effect at high concentrations. The addition of a phosphate group at position 4 of the sugar moiety was the only modification studied so far that produced a pure antagonist with increased antiendotoxin activity. Demonstration of these structural requirements for the antiendotoxin activity of lipid A analogues supports the hypothesis that this effect may be mediated via specific cellular binding sites. Lipid X derivatives may be useful for studying the interaction of endotoxin with cells and their antiendotoxin activity may prove beneficial in the treatment of septicemia.
authors.affiliation: Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: R L
authors.initials: RL
authors.lastname: Danner
authors.forename: A L
authors.initials: AL
authors.lastname: Van Dervort
authors.forename: M E
authors.initials: ME
authors.lastname: Doerfler
authors.forename: P
authors.initials: P
authors.lastname: Stuetz
authors.forename: J E
authors.initials: JE
authors.lastname: Parrillo
mesh_terms: D001424:Bacterial Infections / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D006017:Glycolipids / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008050:Lipid A / Q000494:pharmacology* / Q000627:therapeutic use; D009227:Myristic Acids / Q000032:analysis; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013481:Superoxides / Q000378:metabolism; D014343:Trypan Blue
chemical_list: D004731:Endotoxins; D006017:Glycolipids; D008050:Lipid A; D009227:Myristic Acids; D013481:Superoxides; C009893:beta-hydroxymyristic acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; C044283:lipid X; D014343:Trypan Blue