Immunopharmacological activities of chemically synthesized lipid a-subunit analogue GLA-27 combined with muramyl dipeptide via spacers of different carbon chain length

Abstract

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 lenghts 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. On the other hand, GLA-106 and GLA-107 markedly enhanced non-specific host resistance against Pseudomonas aeroginosa infection compared with GLA-27 and 1-deoxy MDP with lesser activity equivalent to that of GLA-101 and GLA-105.