Effects of backbone structures and stereospecificities of lipid A-subunit analogues on their biological activities.
Among chemically synthesized analogues corresponding to the nonreducing sugar part of lipid A, we have found an analogue (GLA-27) which exhibits Limulus, mitogenic, polyclonal B cell activation (PBA), interferon-inducing, and tumor necrosis factor (TNF)-inducing activities but not pyrogenic activity. The structure of GLA-27 comprises 4-O-phosphono-D-glucosamine with tetradecanoyl and 3-tetradecanoyloxytetradecanoyl (C14-O-(C14] groups as the 3-O- and 2-N-acyl substituents, respectively. Derivatives of GLA-27 with different backbone structures, such as the 1-deoxy, 3-epimeric, 3-amino, and 1-deoxy-3-epimeric derivatives of glucosamine, were chemically synthesized, and their mediator-inducing activities such as interferon- and TNF-inducing activities were investigated in comparison with their B cell activation activities including mitogenic and PBA activities. Among these derivatives, a derivative with a 1-deoxyglucosamine backbone (GLA-40) exhibited stronger B cell activation activities than those of GLA-27 while the mediator-inducing activities of GLA-40 were weaker than those of GLA-27. In addition to these derivatives, stereoisomers of GLA-27 which possess the (R) and (S) forms of C14-O-(C14) as the 2-N-acyl substituent were also synthesized and their biological activities compared. The (S) isomer exhibited much stronger mediator-inducing activities than the (R) isomer. On the other hand, B cell activation activities of the (R) isomer were strong and those of the (S) isomer weak. These results clearly demonstrate that mediator-inducing activities and B cell activation activities can be selectively expressed by modifying the structures of lipid A analogues.
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D006023:Glycoproteins / Q000096:biosynthesis; D007369:Interferon Inducers; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008934:Mitogens; D011817:Rabbits; D013154:Spleen / Q000276:immunology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha
D006023:Glycoproteins; D007369:Interferon Inducers; D008050:Lipid A; D008934:Mitogens; D014409:Tumor Necrosis Factor-alpha; C048988:GLA 27