Biological activities of chemically synthesized analogues of the nonreducing sugar moiety of lipid A

Matsuura, Motohiro; Kojima, Yasuhiko; Jy, Homma; Kubota, Yoshiyuki; Yamamoto, Akihiro; Kiso, Makoto; Hasegawa, Akira

doi:10.1016/0014-5793(84)80131-3

Cited by 70 publications

(18 citation statements)

References 9 publications

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“…As reported in [2,4,5,8], GLA-27 exhibited significant TNF-inducing activity; however, the ac- fig.3). Decreased TNF-inducing activity was observed in GLA-65 with an S-AC group at Cl.…”

Section: Resultssupporting

confidence: 62%

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Effect of chemical modification at C1 of the glucosamine backbone of lipid A‐subunit analog GLA‐27 on manifestation of immunopharmacological activity

et al. 1988

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The effect of chemical modification at the Cl position of GLA-27,4-O-phosphono-D-glucosamine carrying N-3-tetradecanoyloxytetradecanoyl [C,,-0-(C,,)] and 30tetradecanoyl (C,,) groups, was investigated. Replacement by SH or Sacetyl groups of the OH group resulted in the enhancement of mitogenicity but gave rise to a reduction, in macrophagestimulating ability such as induction of tumor necrosis factor and enhancement of phagocytic and cellular acid phosphatase activities. Bisphosphorylation at Cl and C4 resulted in a slight decrease in mitogenicity or almost complete loss of the macrophage-stimulating ability.

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“…As reported in [2,4,5,8], GLA-27 exhibited significant TNF-inducing activity; however, the ac- fig.3). Decreased TNF-inducing activity was observed in GLA-65 with an S-AC group at Cl.…”

Section: Resultssupporting

confidence: 62%

“…Liideritz and C. Galanos (Max-Planck-Institut fiir Immunobiologie, Freiburg, FRG) and used as a positive control. Samples were solubilized in pyrogen-free water by treatment with triethylamine and complexing with bovine serum albumin as described in [2].…”

Section: Synthetic and Natural Compoundsmentioning

confidence: 99%

Effect of chemical modification at C1 of the glucosamine backbone of lipid A‐subunit analog GLA‐27 on manifestation of immunopharmacological activity

et al. 1988

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“…Acyloxyacylated compounds were shown to exhibit stronger activities than the compounds with 3-hydoxytetradecanoic acid [7 -111. Since mediator-inducing and immunomodulating activities were exhibited, though with lesser extent, even by the previous analogues different in positions and numbers of fatty acid substituents [7] or only the nonreducing sugar moiety of lipid A [28], the structural requirement for these activities must be broad.…”

Section: Discussionmentioning

confidence: 99%

Biological activities of analogues of lipid A based chemically on the revised structural model

Kanegasaki

Kojima

Matsuura

et al. 1984

European Journal of Biochemistry

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Lipid A analogues were chemically synthesized based on the model structure recently revised, and biological activities of the analogues were tested. The analogue, (p-I,6)-linked glucosamine disaccharide carrying ester-bound 3-hydroxytetradecanoic acids at 3 and 3' position of reducing and nonreducing glucosamine in addition to amidebound 3-hydroxytetradecanoic acids and glycosidic-linked and ester-linked phosphate groups, showed much stronger activities for mediator inducing and immunomodulating as well as endotoxic activities than those exhibited by the previously synthesized analogues based on the old model. Among the activities tested, induction of interferon and tumor necrosis factor as well as mitogenicity, adjuvanticity and pyrogenicity were, however, not expressed so strongly as natural lipid A used as controls. In contrast, the analogue exhibited comparable activities to those of control lipid A in the test of lethal toxicity to mice and gelating activity of Limulus amebocyte lysate. Other synthetic analogues carrying a phosphate group showed comparable, slightly stronger or weaker activities depending on the test, but nonphosphorylated analogue exhibited no apparent or only very weak activities.It is well established that lipid A component of lipopolysaccharides of gram-negative bacteria is responsible for most, if not all, various biological and endotoxic activities including lethal toxicity, pyrogenicity, immunomodulating activities, and the activities to induce various mediators [I]. The chemical structure of the lipid A backbone in many bacteria appears to be identical and consists of a (/3-1,6)-linked D-glucosamine disaccharide which carries phosphate residues in the positions of 1 and 4 as well as amide-bound and ester-bound D-3-hydroxy and/or acyloxy fatty acids [2], although a number of minor differences in structure are known in lipid A derived from various bacteria. It is also known that isolated free lipid A is a mixture of congeners.To confirm lipid A structure and to establish the structure responsible for the functions, compounds based on the proposed structure were recently chemically synthesized [3 -51 and their biological activities were investigated in many laboratories [6-121. Although some of the synthetic analogues have been reported to show significant biological activities such as interferon inducing [7] as well as mitogenic and adjuvant activities [6, 7, 1 I], the activity of the analogues, if any [6-121 were much weaker than natural lipid A.More recently, locations of ester-linked 3-hydroxytetradecanoic acid (or acyloxy fatty acid) of lipid A from Escherichia coli, Salmonella typhimurium and Proteus mirahilis were reinvestigated. The results disclosed that the locations were not at the 3,4 and 6' positions as presumed previously but at the 3 and 3' positions of diglucosamine unit 113-151. The compound with such altered structure, therefore, was hoped to enhance biological activities and represent comparable activities to natural lipid A. Based on the modified structure, analogue...

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“…As reported previously [25], significant mitogenic activity was found in GLA-27 (type-I), which is a 4-0-phosphorylated GlcN derivative carrying Nlinked c14-o-(c14) and 3-O-linked C14 groups. Replacement of the N-linked fatty acid substituents, C14-O-(C14), in GLA-27 for other substituents such as CI4 or C140H groups resulted in loss of mitogenic activity as seen in GLA-26 (compound 2 in the previous reports [24,25]), GLA-44 and GLA-46 of type I compounds. A 1-deoxy derivative (type 11) of GLA-27, GLA-40, showed stronger activity than GLA-27.…”

Section: Effect Of Fatty Acid Substituents In 4-0-phosphorylated Glcnmentioning

confidence: 83%

Structural requirements for inducing in vitro B lymphocyte activation by chemically synthesized derivatives related to the nonreducing D‐glucosamine subunit of lipid A

et al. 1986

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Mitogenic and polyclonal B cell activation (PBA) activities of 16 synthetic compounds related to the nonreducing D-glucosamine (GlcN-II) subunit of lipid A were investigated. Among compounds possessing the GlcN backbone, a 4-O-phosphorylated GlcN derivative carrying N-linked 3-tetradecanoyloxytetradecanoyl [C14-O-(C14)] and 3-O-linked tetradecanoyl (C14) groups, GLA-27, expressed the highest degree of both activities. Omission of the 3-O-linked C14 group from GLA-27 and transfer of the C14 group to the C-6 position induced critical changes in expression of activities. Both 4-O-phosphorylated compounds carrying an N-linked C14 or 3-hydroxytetradecanoyl (C14OH) group instead of the C14-O-(C14) group in GLA-27 showed no detectable activity. Substituting a 3-O-linked C14 group in GLA-27 for the C14-O-(C14) group also markedly decreased mitogenic and PBA activities. Change of phosphorylation site from the C-4 to the C-6 position and bisphosphorylation at the C-4 and C-6 positions induced somewhat weak depression. Much weaker activities were observed in a compound carrying N-linked 3-dodecanoyloxydodecanoyl [C12-O-(C12)] and 3-O-dodecanoyl (C12) as fatty acid substituents. No detectable activity was seen in a compound carrying N-linked 3-hexadecanoyloxyhexadecanoyl [C16-O-(C16)] and 3-O-hexadecanoyl (C16), indicating that the most suitable carbon chain length for expressing the activities is C14. Regarding structural change of the GlcN backbone, a 1-deoxy derivative of GLA-27 exhibited stronger activity than did GLA-27 itself. Mitogenic and PBA activity of GLA-27 were stronger than those of lipid X, which corresponds to the reducing D-GlcN (GlcN-I) subunit of Escherichia coli lipid A and is a 1-O-phosphorylated GlcN derivative carrying N- and 3-O-linked C14OH groups. These results indicate that N-linked acyloxyacyl and 3-O-linked acyl groups and phosphorylation are critical for expressing both mitogenic and PBA activities.

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Biological activities of chemically synthesized analogues of the nonreducing sugar moiety of lipid A

Cited by 70 publications

References 9 publications

Effect of chemical modification at C1 of the glucosamine backbone of lipid A‐subunit analog GLA‐27 on manifestation of immunopharmacological activity

Effect of chemical modification at C1 of the glucosamine backbone of lipid A‐subunit analog GLA‐27 on manifestation of immunopharmacological activity

Biological activities of analogues of lipid A based chemically on the revised structural model

Structural requirements for inducing in vitro B lymphocyte activation by chemically synthesized derivatives related to the nonreducing D‐glucosamine subunit of lipid A

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