Agonistic and antagonistic activities of bacterially derived Rhodobacter sphaeroides lipid A: comparison with activities of synthetic material of the proposed structure and analogs

Rose, Jeffrey; Christ, William J.; Bristol, John R.; Kawata, Tsutomu; Rossignol, Daniel P.

doi:10.1128/iai.63.3.833-839.1995

Cited by 52 publications

(38 citation statements)

References 29 publications

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“…The activity of E5531 places it among the most potent antagonists of LPS ever reported. In monocytes, E5531 was approximately 26,000 fold more active than Lipid X and 500 fold more active than Lipid IV A (Table 1) and demonstrates similar or better in vitro antagonistic activity when compared to results previously reported for R. Sphaeroides lipid A (Rose et al, 1995).…”

Section: Discussionsupporting

confidence: 78%

“…Related studies from us and other laboratories suggest that other synthetic and biologically-derived analogues of bacterially-derived non-toxic lipid As from both R. capsulatus and from R. sphaeroides can more potently antagonize the toxic eects of LPS (Loppnow et al, 1990;Lynn & Golenbock, 1992;Qureshi et al, 1991;Rose et al, 1995;Takayama et al, 1989). However, despite their antagonistic properties, some bacterially-derived materials also exhibited agonistic activity in human and/or animal model systems (Rose et al, 1995). The activity of E5531 places it among the most potent antagonists of LPS ever reported.…”

Section: Discussionmentioning

confidence: 97%

“…Cellular activation of hematopoietic cells by endotoxin results in release of a variety of cytokines and other cellular mediators likely to play a major role in induction of septic shock. The antagonistic potency of E5531 against LPS-induced cellular activation could be demonstrated by assaying any of a variety of cytokines in several systems (Christ et al, 1995). Here, we measured release of TNF-a in human whole blood and monocytes (Figures 2A, 3 and Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, E5531 inhibited LPS-induced E-selectin expression in HUVEC (Figure 8). Taken together, antagonism of this wide variety of cytokines (Christ et al, 1995) and other biological responses as well as inhibition of NF-kB activation by LPS (Christ et al, 1992) demonstrates that E5531 antagonizes activation of cells by LPS.…”

Section: Discussionmentioning

confidence: 99%

“…These ®ndings have motivated us to develop a speci®c and non-toxic synthetic antagonist for the actions of LPS for the treatment of septic shock. E5531 has been described as a potent in vitro and in vivo antagonist of LPS (Christ et al, 1995;Kobayashi et al, 1998). This report demonstrated further in vitro biological characterization of E5531 in a variety of experimental systems making it a promising potential therapeutic as an anti-endotoxin drug for the treatment of sepsis and septic shock.…”

Section: Introductionmentioning

confidence: 99%

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E5531, a synthetic non‐toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide

Kawata

Bristol

Rossignol

et al. 1999

British J Pharmacology

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1 The major pathological responses to Gram-negative bacterial sepsis are triggered by endotoxin or lipopolysaccharide. As endotoxin is shed from the bacterial outer membrane, it induces immunological responses that lead to release of a variety of cytokines and other cellular mediators. As part of a program aimed at developing a therapeutic agent for septic shock, we have developed E5531, a novel synthetic lipopolysaccharide antagonist. 2 As measured by release by tumour necrosis factor-a, human monocytes or whole blood can be activated by lipopolysaccharide, lipid A, and lipoteichoic acid (from Gram-positive bacteria). E5531 potently antagonizes activation by all these agents while itself being devoid of agonistic activity. 3 The inhibitory activity of E5531 was dependent on time of addition. When 10 nM E5531 was added simultaneously with lipopolysaccharide or 1 ± 3 h before addition of lipopolysaccharide, production of tumour necrosis factor-a was inhibited by more than 98%. The addition of E5531 1 h after lipopolysaccharide reduced the ecacy of E5531 by 47%. 4 Antagonistic activity of E5531 was speci®c for lipopolysaccharide as it was ineective at inhibiting interferon-g mediated NO release of RAW 264.7 cells, phorbor 12-myristate 13-acetate stimulated superoxide anion production in human neutrophils, concanavalin A stimulated mitogenic activity in murine thymocytes and tumor necrosis factor-a induced E-selectin expression in human umbilical vein endothelial cells. 5 E5531 as well as MY4, an anti-CD14 antibody, inhibited radiolabelled lipopolysaccharide binding in human monocytes. 6 These results support our contention that E5531 is a potent antagonist of lipopolysaccharideinduced release of tumour necrosis factor-a and other cellular mediators and may be an eective therapeutic agent for human septic shock due to Gram-negative bacteria.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

E5531, a synthetic non‐toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide

Kawata

Bristol

Rossignol

et al. 1999

British J Pharmacology

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The 2‐Aminogluconate Isomer of Rhizobium sin‐1 Lipid A Can Antagonize TNF‐α Production Induced by Enteric LPS

et al. 2006

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The naturally occurring lipopolysaccharide (LPS) from Rhizobium sin-1, a nitrogen-fixing bacterial species, can prevent the induction of the tumor necrosis factor TNF-alpha induced by enteric LPS. The proximal saccharide moiety of R. sin-1 lipid A can exist in two forms, namely as a 2-aminogluconolactone or 2-aminogluconate. As it is unknown which of these forms is responsible for the antagonistic properties of R. sin-1 lipid A, compound 4 was prepared, and its inflammatory properties were studied. This compound contains a methyl ether at the C-5 hydroxyl, which prevents lactonization and therefore is ideally suited to determine whether the 2-aminogluconate possesses antagonistic properties. Compound 4 was synthesized by a highly convergent approach with a key disaccharide building block functionalized with a set of orthogonal protecting groups. The novel synthetic compound lacks proinflammatory properties, as indicated by an absence of TNF-alpha protein production. This compound was, however, able to antagonize the production of TNF-alpha induced by enteric LPS; this indicates that the 2-aminogluconate form of R. sin-1 lipid A is responsible for its biological properties.

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Thermophiles as Potential Source of Novel Endotoxin Antagonists: the Full Structure and Bioactivity of theLipo‐oligosaccharide from Thermomonas hydrothermalis

Lorenzo¹,

Paciello

Fazio

et al. 2014

ChemBioChem

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Thermomonas hydrothermalis is a Gram-negative thermophilic bacterium that is able to live at 50 °C. This ability is attributed to chemical modifications, involving those to bacterial cell-wall components, such as proteins and (glyco)lipids. As the main component of the outer membrane of Gram-negative bacteria, lipopolysaccharides (LPSs) are exposed to the environment, thus they can undergo structural chemical changes to allow thermophilic bacteria to live at their optimal growth temperature. Furthermore, as one of the major target of the eukaryotic innate immune system, LPS elicits host immune response in a structure-dependent mode; thus the uncommon chemical features of thermophilic bacterial LPSs might exert a different biological action on the innate immune system-an antagonistic effect, as shown in studies of LPS structure-activity relationship in the ongoing research into antagonist LPS candidates. Here, we report the complete structural and biological activity analysis of the lipo-oligosaccharide isolated from Thermomonas hydrothermalis, achieved by a multidisciplinary approach (chemical analysis, NMR, MALDI MS and cellular immunology). We demonstrate a tricky and interesting structure combined with a very interesting effect on human innate immunity.

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Agonistic and antagonistic activities of bacterially derived Rhodobacter sphaeroides lipid A: comparison with activities of synthetic material of the proposed structure and analogs

Cited by 52 publications

References 29 publications

E5531, a synthetic non‐toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide

E5531, a synthetic non‐toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide

The 2‐Aminogluconate Isomer of Rhizobium sin‐1 Lipid A Can Antagonize TNF‐α Production Induced by Enteric LPS

Thermophiles as Potential Source of Novel Endotoxin Antagonists: the Full Structure and Bioactivity of theLipo‐oligosaccharide from Thermomonas hydrothermalis

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