J. Biochem, 1986, Vol. 99, No. 5 1377-1384
© 1986 Japanese Biochemical Society
research-article |
Effects of Backbone Structures and Stereospecificities of Lipid A-Subunit Analogues on Their Biological Activities1
*The Kitasato Institute Shirokane, Minato-ku, Tokyo 108
**School of Pharmaceutical Science, Kitasato University Shirokane, Minato-ku, Tokyo 108
***Chugai Pharmaceutical Co., Ltd. Takada, Toshima-ku, Tokyo 171
****Department of Agricultural Chemistry Gifu, Gifu 501–11
2To whom correspondence should be addressed
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-tetra-decanoyloxytetradecanoyl (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 3-O- and 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.
1This work was supported in part by Grants-in-Aid for Scientific Research (Nos. 59570651 and 60114002) from the Ministry of Education, Science and Culture of Japan and Research Grant No. 59-296 from the Ishida Foundation.