title: Structural basis for endotoxic and antagonistic activities: investigation with novel synthetic lipid A analogs.
abstract: Our early work using homogeneous synthetic preparations demonstrated the presence of a lipid A analog which antagonizes endotoxic activities of LPS and lipid A. The first example was a tetraacylated biosynthetic precursor, now known as precursor Ia or lipid IVa, that contains four 3-hydroxytetradecanoyl moieties linked to the bisphosphorylated disaccharide backbone common to the endotoxic hexa-acyl Escherichia coli lipid A. Various compounds with both endotoxic and antagonistic activities have subsequently been reported from either natural or synthetic sources, but little is known about the factors determining the type of the activities of the respective compounds. To approach this issue, we have synthesized a series of lipid A analogs with various numbers and chain lengths of acyl groups on the backbone. Some were prepared by the aid of a novel affinity separation procedure. The phosphate moieties were also synthetically replaced. Biological tests showed that at least three acyl groups are required for antagonistic activity but one or even both of the phosphates can be replaced with other acidic moieties without losing the activity. The effect of Kdo residues linked to lipid A is also briefly discussed. Molecular dynamics calculations reasonably explain possible conformations required for the biological activity.
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan. skus@chem.sci-osaka-u.ac.jp
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kusumoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Fukase
authors.forename: Mikayo
authors.initials: M
authors.lastname: Kataoka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yoshizaki
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sato
authors.forename: Masato
authors.initials: M
authors.lastname: Oikawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Suda
mesh_terms: D001773:Blood Cells / Q000378:metabolism; D002846:Chromatography, Affinity; D003198:Computer Simulation; D003470:Culture Media; D004731:Endotoxins; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis / Q000096:biosynthesis; D008033:Limulus Test; D008050:Lipid A / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D008968:Molecular Conformation; D015394:Molecular Structure; D009010:Monte Carlo Method; D012015:Reference Standards; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis
chemical_list: D003470:Culture Media; D004731:Endotoxins; D015850:Interleukin-6; D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha