Enhancement of nonspecific resistance to viral infection by chemically synthesized lipid A-subunit analogs with different backbone structures and acyl groups

Ikeda, Satoru; Kumazawa, Yoshio; Nishimura, Chiaki; Nakatsuka, Mitsunobu; Jy, Homma; Kiso, Makoto; Hasegawa, Akira

doi:10.1016/0166-3542(88)90029-0

Cited by 10 publications

(4 citation statements)

References 19 publications

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“…Synthetic lipid A subunits of the nonreducing sugar moiety such as GLA-27 and GLA-60 were reported to activate B cells and macrophages and to induce release of mediators including gamma interferon and tumor necrosis factor (TNF) at nontoxic doses (for a review, see reference 5). The analogs were also found to be active in enhancing host resistance to microbial and viral infections in normal and myelosuppressed mice (5)(6)(7). Synthetic lipid X, the prototype reducing sugar moiety of lipid A, has been found to exhibit little (22) or none of the immunostimulatory activity (1,14) previously attributed to the natural compound extracted from Escherichia coli mutant MN7 (3).…”

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confidence: 99%

SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis

Lam

Schütze

Hildebrandt

et al. 1991

Antimicrob Agents Chemother

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SDZ MRL 953, a new synthetic monosaccharidic lipid A, was investigated in vitro and in vivo for immunopharmacological activities. In experimental models of microbial infections, the compound was highly protective when it was administered prophylactically either once or three times to myelosuppressed or immunocompetent mice. The 50% effective doses of SDZ MRL 953 varied with the infectious agents and the route of its administration. In all cases, the 50% effective doses were about 103 times higher than those obtained with endotoxin from Salmonella abortus equi. SDZ MRL 953 was, however, less toxic than lipopolysaccharide by a factor of 104 to >7 x 105 times in galactosamine-sensitized mice. The compound was also an effective inducer of tolerance to endotoxin. Hence, repeated dosing with the compound induced a transient resistance (.1 week) to lethal challenges with endotoxin. In vitro, the compound was devoid of intrinsic antimicrobial activity, but it moderately induced the release of cytokines from monocytes and primed human neutrophils for the enhanced production of reactive oxygen metabolites in response to a soluble stimulus. The results presented here suggest that SDZ MRL 953 may be useful in a clinical setting for enhancing resistance to infections, particularly in patients undergoing myelosuppressive chemotherapy or irradiation, and for the prophylaxis of endotoxin shock.Lipopolysaccharides (LPS) are common constituents of cell walls of gram-negative bacteria. They can cause a whole array of pathophysiological effects and are also the most powerful immunostimulants known. It is generally accepted that the lipid A moiety, the terminal acylated P(1-6)glucosamine disaccharide-1,4'-diphosphates of endotoxin, is responsible for immunopharmacological activity and induction of endotoxicity, such as changes in leukocyte count, disseminated intravascular coagulation, and multiorgan failure leading to irreversible shock and death (5,21,25).Extensive studies have unsuccessfully addressed the possibility of harnessing the immunopharmacological activities of endotoxins by using various detoxifying approaches (17,20). The elucidation of the correct structure of lipid A (8, 26) and the subsequent success in the total synthesis of biologically active lipid A and analogs (9-12, 27) have rekindled interest in the possibility of separating the immunostimulatory and toxic moieties of endotoxin. Efforts to identify beneficial immunostimulatory lipid A derivatives have concentrated on synthetic analogs representing both the nonreducing (10-12) and reducing sugar moieties, such as lipids X and Y (15,27). Synthetic lipid A subunits of the nonreducing sugar moiety such as GLA-27 and GLA-60 were reported to activate B cells and macrophages and to induce release of mediators including gamma interferon and tumor necrosis factor (TNF) at nontoxic doses (for a review, see reference 5). The analogs were also found to be active in enhancing host resistance to microbial and viral infections in normal and myelosuppressed mice (5-7). Synth...

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confidence: 99%

SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis

Lam

Schütze

Hildebrandt

et al. 1991

Antimicrob Agents Chemother

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“…Taken together, our results and these observations suggest that complicated mechanisms may exist in the regulation of the response to LPS challenge. Although neutrophils and TNF have been considered to exacerbate acute lung injury, both may have beneficial effects on the host defense against infections (11,28). In the present study, SDZ may have induced certain mediators other than TNF that are responsible for attenuating the effects on lung injury.…”

Section: Discussionmentioning

confidence: 60%

“…SDZ was found to stimulate macrophages to release cytokines such as interleukin-6, interleukin-8, TNF, and colonystimulating activity in a previous in vitro study (16). The other lipid A analogs, such as GLA-27 and GLA-60, were also found to be active in enhancing host resistance to microbial and viral infections in mice when they were administered 1 to 3 days before inoculation (11,12). These analogs were reported to activate B cells and macrophages and to induce the release of mediators including gamma interferon and TNF (9).…”

Section: Discussionmentioning

confidence: 87%

“…In contrast, synthetic lipid A subunits of nonreducing sugar moieties, such as GLA-27 and GLA-60, have been reported to induce the release of mediators including gamma interferon and tumor necrosis factor (TNF) at nontoxic doses (9). These analogs have also been found to be active in enhancing host resistance to microbial and viral infections in healthy and myelosuppressed mice (11,12). These observations suggest that lipid A analogs may enhance the host defense against infections by inducing various cytokines.…”

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confidence: 88%

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Effects of pretreatment with SDZ MRL 953, a novel immunostimulatory lipid A analog, on endotoxin-induced acute lung injury in guinea pigs

Nakamura

Ishizaka

Urano

et al. 1995

Clin Diagn Lab Immunol

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SDZ MRL 953 (SDZ), a novel immunostimulatory lipid A analog, has been reported to have immunopharmacological activities similar to those of lipopolysaccharide (LPS) but to have little of the toxicity of LPS. We investigated the effects of pretreatment with SDZ on Escherichia coli endotoxin-induced acute lung injury in guinea pigs. Four experimental groups consisted of saline control (n ‫؍‬ 16), SDZ (؊12 h) plus LPS (2 mg/kg of SDZ per kg of body weight injected intravenously 12 h before intravenous injection of 2 mg of LPS per kg; n ‫؍‬ 15), SDZ (؊10 min) plus LPS (SDZ injected 10 min before LPS injection; n ‫؍‬ 10), and LPS alone (n ‫؍‬ 16). The animals were sacrificed, and lung tissue was sampled 4 h after LPS or saline infusion. Lung injury was assessed by measuring the wet weight-to-dry weight ratio and the level of 125 I-labeled albumin accumulation in bronchoalveolar lavage fluid relative to that in plasma. In the SDZ (؊12 h) plus LPS group, these two parameters of acute lung injury were decreased compared with those in the LPS alone group. However, they were not decreased in the SDZ (؊10 min) plus LPS group. We conclude that SDZ attenuates endotoxininduced acute lung injury when it is administered 12 h before LPS injection. The attenuating effects of SDZ are speculated to be due to down regulation of the response to endotoxin rather than to receptor blocking.

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Structure-Activity Relationship of Chemically Synthesized Nonreducing Parts of Lipid a Analogs

Matsuura

Kumazawa

1990

Endotoxin

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Enhancement of nonspecific resistance to viral infection by chemically synthesized lipid A-subunit analogs with different backbone structures and acyl groups

Cited by 10 publications

References 19 publications

SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis

SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis

Effects of pretreatment with SDZ MRL 953, a novel immunostimulatory lipid A analog, on endotoxin-induced acute lung injury in guinea pigs

Structure-Activity Relationship of Chemically Synthesized Nonreducing Parts of Lipid a Analogs

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