Synthetic lipid A with endotoxic and related biological activities comparable to those of a natural lipid A from an Escherichia coli re-mutant

Abstract

A synthetic compound (506), 0(1-6) D-glucosamine disaccharide 1,4'-bisphosphate, which is acylated at * Corresponding author. (08:K27, Re-mutant) in both effective dose and degree of stimulation. However, compound 406, like the biosynthetic lipid A precursor, was far less active in characteristic endotoxic properties such as pyrogenicity and the activity to prepare the local Shwartzman reaction, though the compound had as high a lethal toxicity as F515 lipid A for mice loaded with galactosamine (5). Galanos et al. (6) have reported essentially the same results in experiments with the same synthetic preparations. The marked differences noted between the synthetic compound, 406, and the natural product, F515 lipid A, regarding biological activities that more or less characterize endotoxic lipopolysaccharide (LPS) and its lipid A moiety have been assumed to be attributable to the following fact: all four acyl groups bound to the amino groups at C-2 and C-2' positions 225

The significance of the hydrophilic backbone and the hydrophobic fatty acid regions of lipid a for macrophage binding and cytokine induction

“…Further, lipid A of Rhodobacter sphaeroides, which possesses the enterobacterial hydrophilic backbone but only five fatty acids of unusual constitution [34], also strongly competes with the binding of 125I-LPS to mouse cells (Kirikae, T., Schade, F.U., Kirikae, F., Qureshi, N., Takayama, K., and Rietschel, E.Th., unpublished results) although it expresses only very low toxicity and cytokine induction capacity [36]. Consistent with this concept, and as shown here, monophosphoryl partial structures possess a considerably lower affinity to cells, resulting in low bioactivity [10,14,15,31,32,37,38]. On the other hand, spacing the glycosidic phosphoryl group from the backbone by an oxyethyl group does apparently not decrease the capacity of lipid A to bind to cells and does not change endotoxic activity.…”

Interpretation of biological activity data of bacterial endotoxins by simple molecular models of mechanism of action

“…1) was built with the biopolymer module of insight ii molecular modelling program, version 97.0 [70] using structural information from previous modelling studies [37,38,41] and NMR experiments [39,40]. Conformations of b-(1,6) interglycosidic and C6-C5 bond linkages in the LA-15-PP were explored by full conformational search over three independent torsion angles 6 ,C 5 ,O) by applying an harmonic restraint potential to {r,c,f}. Formal charge of 21e (consistent with the level of ionization under physiological conditions) was assigned to each phosphate group.…”

Biological Activities of Lipopolysaccharide‐Like Substance (LLS) Extracted from Leptospira interrogans Serovar canicola Strain Moulton

“…In general, it is considered that the active principle of LPS is a lipid A, which is composed of a disaccharide unit, acylated fatty acids, and phosphates. The ability to produce the Shwartzman reaction appears to require Complete lipid A (11,15), and monosaccharide analogs of lipid A possess pyrogenicity and lethal toxicity (17,24), whereas even compounds with chemical structures different from that of lipid A exhibit mitogenicity and adjuvanticity. It is not known if leptospiral LPS has a part corresponding to the lipid A region, but if it is present, it seems to differ from the chemical structure of lipid A of typical LPS.…”