Structure-activity relationship of lipid A: comparison of biological activities of natural and synthetic lipid A's with different fatty acid compositions.
To investigate the structure-activity relationships, various biological activities, including pyrogenicity, lethal toxicity, elicitation of Shwartzman reaction, mitogenicity and tumor necrosis factor (TNF)-inducing activity, were compared among natural and synthetic lipid A's differing in fatty acid composition. In all these tests, natural lipid A's from Escherichia coli and Salmonella minnesota and synthetic LA-15-PP, which carries 3-hydroxy- and 3-acyloxy-tetradecanoyl groups at the 2, 3 and 2', 3' positions, respectively, showed the strongest activities among the tested lipid A's. In contrast, LA-16-PP, in which the amide-bound 3-hydroxytetradecanoic acid at position 2 of LA-15-PP is replaced by 3-hexadecanoyloxytetradecanoic acid, exhibited lower activity than LA-15-PP and natural lipid A's. Although LA-16-PP has been assumed to have a typical Salmonella lipid A structure (and, in fact, it has a structure corresponding to one of the components of Salmonella lipid A), the activity of this synthetic compound was not comparable to that of natural Salmonella lipid A. LA-17-PP, in which tetradecanoic acid is the sole fatty acid component, exhibited relatively strong mitogenicity and TNF-inducing activity, but very low pyrogenicity. The activities of LA-18-PP, which has ester-bound tetradecanoic acid and amide-bound 3-hydroxytetradecanoic acid, were lower than those of LA-17-PP. The results indicate that the differences in fatty acid composition of lipid A's have important influences on the biological activities studied.
Kanegasaki
S
S
Tanamoto
K
K
Yasuda
T
T
Homma
J Y
JY
Matsuura
M
M
Nakatsuka
M
M
Kumazawa
Y
Y
Yamamoto
A
A
Shiba
T
T
Kusumoto
S
S
D000818:Animals; D000906:Antibodies; D003429:Cross Reactions; D000939:Epitopes / Q000032:analysis; D005227:Fatty Acids / Q000032:analysis / Q000502:physiology*; D005260:Female; D005334:Fever / Q000139:chemically induced; D006023:Glycoproteins / Q000032:analysis; D008033:Limulus Test; D008050:Lipid A / Q000032:analysis / Q000138:chemical synthesis / Q000276:immunology / Q000502:physiology* / Q000633:toxicity; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011817:Rabbits; D012475:Salmonella / Q000276:immunology; D012790:Shwartzman Phenomenon / Q000139:chemically induced; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha
D000906:Antibodies; D000939:Epitopes; D005227:Fatty Acids; D006023:Glycoproteins; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha