Immunopharmacological activities of chemically synthesized lipid A-subunit analogue GLA-27 combined with muramyl dipeptide via spacers of different carbon chain length.
A lipid A-subunit analogue GLA-27, a 4-O-phosphono-D-glucosamine derivative carrying 3-O-tetradecanoyl and N-3-tetradecanoyloxytetradecanoyl groups, exhibited significant biological activities but no detectable pyrogenicity or local Shwarzman activity. In order to synthesize compounds combining GLA-27 with muramyl dipeptide (MDP), the OH group at the C6 position of GLA-27 was first succinylated. A compound which combined a succinylated GLA-27 (GLA-101) with 1-deoxy N-acetyl-muramyl-L-alanyl-D-isoglutamine methyl ester (1-deoxy MDP) via spacers of different carbon chain lengths of 5, 11 and 15, termed GLA-105, GLA-106 and GLA-107, respectively, and their biological activities were investigated. Intraperitoneal administration of combined preparations with spacers, GLA-105 and GLA-107, induced much higher phagocytic activity in peritoneal macrophages than GLA-27, GLA-101 and 1-deoxy MDP. The activity of GLA-106 did not increase by the combination. In induction of natural killer (NK) activity in peritoneal cells, GLA-105 and GLA-107 were significantly more active than 1-deoxy MDP but only comparable with GLA-27. GLA-101 showed stronger NK activity than GLA-27. The activity of GLA-106 was stronger than 1-deoxy MDP but weaker than GLA-27, GLA-105 and GLA-107. Mitogenic, interferon-inducing and tumor necrosis factor-inducing activities decreased by combining GLA-101 with 1-deoxy MDP. GLA-101, GLA-105 and GLA-107 strongly inhibited the formation of lesions on the tail of mice infected with Vaccinia virus. The activity was almost equivalent to that of GLA-27.(ABSTRACT TRUNCATED AT 250 WORDS)
Ikeda
S
S
School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Kumazawa
Y
Y
Sai
K
K
Nishimura
C
C
Nakatsuka
M
M
Homma
J Y
JY
Yamamoto
A
A
Kiso
M
M
Hasegawa
A
A
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D005260:Female; D007109:Immunity / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects; D007372:Interferons / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000998:Antiviral Agents; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C048988:GLA 27; D007372:Interferons