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: R L Danner, A L Van Dervort, M E Doerfler, P Stuetz, J E Parrillo
• Journal: Pharmaceutical research (Pharm Res) Vol. 7 Issue 3 Pg. 260-3 (Mar 1990) ISSN: 0724-8741 [Print] United States
• PMID: 2160074 (Publication Type: Journal Article)

Chemical References

• Endotoxins
• Glycolipids
• Lipid A
• Myristic Acids
• Superoxides
• beta-hydroxymyristic acid
• N-Formylmethionine Leucyl-Phenylalanine
• lipid X
• Trypan Blue

Topics

• Bacterial Infections (drug therapy)
• Chemical Phenomena
• Chemistry
• Endotoxins (antagonists & inhibitors)
• Glycolipids (pharmacology)
• Humans
• In Vitro Techniques
• Lipid A (pharmacology, therapeutic use)
• Myristic Acids (analysis)
• N-Formylmethionine Leucyl-Phenylalanine (pharmacology)
• Neutrophils (drug effects)
• Sepsis (drug therapy, microbiology)
• Superoxides (metabolism)
• Trypan Blue