For the past ten years, several groups were engaged in synthetic studies of lipid A, namely the lipid portion of bacterial lipopolysaccharides (LPS) that has been assumed to be the bioactive center of LPS, but has not been unanimously approved. Among them, Shiba, Kusumoto, and colleagues, Osaka, Japan have synthesized most energetically and successfully a variety of counterparts of lipid As, biosynthetic lipid A precursors, and their analogs. The endotoxic and related bioactivities of these synthetic compounds were studied by Japanese and German groups, including ours. In 1985, one of the compounds, having an acylation and phosphorylation pattern in beta(1-6)-D-glucosamine disaccharide which was proposed for Escherichia coli F515 lipid A was found to be exhibit full endotoxic and related bioactivities identical to those of the bacterial product. The study was extended by synthesis and examination of bioactivities of variously acylated D-glucosamine di- and monosaccharide phosphates, which correspond to structural components of lipid As, and their analogs or derivatives. Thus, structural requirements have been fairly well elucidated. In this article, first we will review the progress of synthetic and biological studies, with particular emphasis on chemical structure--bioactivities relationships of lipid As, and then we will discuss possible usefulness of some less or nontoxic lipid A-related synthetic compounds in clinical and preventive medicine.

Structural requirements of lipid A for endotoxicity and other biological activities.

Sensing of bacteria: NOD a lonely job

Muropeptides are breakdown products of peptidoglycan (PGN) of Gram-negative and Gram-positive bacteria. They are released during bacterial growth and division, as part of the host response by lysozyme and amidases, or upon antibiotic treatment. After phagocytosis of bacteria or bacterial breakdown products by host immune cells, the muropeptides trigger intracellular signaling cascades, leading to altered gene expression and activation of the immune response. Numerous muropeptides and derivatives have been synthesized chemically to characterize their immunostimulatory effects and adjuvant activity. Muramyl dipeptide, a natural partial structure of PGN, is the minimal structure with adjuvant activity. This review discusses the structure and occurrence of muropeptides and gives a broad overview of their inflammatory and adjuvant activity and the possible involvement of receptors in these responses.

/pdf/mdp-and-other-muropeptides-direct-and-synergistic-effects-on-swbth1qscf.pdf

MDP and other muropeptides--direct and synergistic effects on the immune system.

Bacterial Endotoxin:Molecular Relationships Between Structure and Activity

Approaches to treat cancer with therapeutic vaccination have made significant progress. In order to induce efficient antitumor immunity, a vaccine should target and activate antigen-presenting cells, such as the dendritic cell, while delivering the tumor-derived antigen of choice. Conjugates of synthetic peptides and ligands of pattern-recognition receptors (PRRs) combine these features and, given their synthetic nature, can be produced under GMP conditions. Therefore, conjugation of antigenic peptides to potent PRR ligands is a promising vaccination approach for the treatment of cancer. This review focuses on the different PRR families that can be exploited for the design of conjugates and explores the results obtained so far with PRR ligands conjugated to antigen. The uptake and processing of Toll-like receptor ligand-peptide conjugates are discussed in more detail, as well as future directions that may further enhance the immunogenicity of conjugates.

TLR ligand-peptide conjugate vaccines: toward clinical application.

Intravenous injection of muramyl dipeptide (MDP) and Salmonella lipopolysaccharides (LPS) enhanced lethal toxicity of the LPS in C57BL/6 mice. This was true for S (smooth)- and R (rough)-form LPS and free lipid A. Enhancement of toxicity was maximum when the LPS was administered 4 h after MDP, at which time the lethal doses for 50% of mice of S- and R-form LPS and free lipid A were between 1 and 10 micrograms, compared with more than 100 micrograms in normal animals. This sensitization was absent in endotoxin-resistant C3H/HeJ mice. Lethality usually commenced 15 h after LPS injection and was complete after 72 h. Higher doses of some S-form LPS (100 micrograms or more) administered 4 h after MDP led to a strong anaphylactoid reaction within 10 to 20 min of injection, with lethal outcomes in less than 1 h after LPS administration. This early anaphylactoid reaction was observed for various mouse strains, including LPS-resistant C3H/HeJ mice, but it was very weak or completely absent with R-form LPS or free lipid A even in concentrations of up to 1,000 micrograms. A strong anaphylactoid reaction comparable to that seen with S-form LPS was also obtained, after MDP treatment, with an LPS of low toxicity prepared from Bacteroides gingivalis. It is noteworthy that oral administration of MDP also contributed to the anaphylactoid reaction and enhanced the late-phase lethality of LPS. The present findings strongly suggest that the early- and late-phase reactions induced by MDP and LPS are caused by different mechanisms.

Enhancement of endotoxin lethality and generation of anaphylactoid reactions by lipopolysaccharides in muramyl-dipeptide-treated mice.

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Enhancement of endotoxin lethality and generation of anaphylactoid reactions by lipopolysaccharides in muramyl-dipeptide-treated mice.