title: Non-specific protective activity of synthetic lipid A-subunit analogs against microbial infections is influenced by their 2-N- and 3-O-linked acyl substituents in the D-glucosamine backbone.
abstract: Non-specific protective activities against vaccinia virus (VV) and Pseudomonas aeruginosa infections as well as interferon (IFN)-inducing, natural killer (NK) cell and macrophage activation activities of chemically synthesized lipid A-subunit analogs were investigated. The analogs are 4-O-phosphono-D-glucosamine derivatives carrying different 2-N- and 3-O-linked acyl substituents such as (R)-3-tetradecanoyloxytetradecanoyl (C14-O-(C14)), (R)-3-hydroxytetradecanoyl (C14-OH) and tetradecanoyl (C14) groups. Compounds GLA-59 and GLA-60, which possess C14-OH and C14-O-(C14) groups as their acyl substituents, showed stronger IFN-inducing and anti-vaccinia virus activities than GLA-27 and GLA-68, which possess a C14 group instead of the C14-OH group in GLA-59 and GLA-60, although NK cell activation activity was similarly high in all of these compounds. In protective activity against P. aeruginosa infection and macrophage activation activity, GLA-60 and GLA-68, which carry a C14-O-(C14) group at the 3-O-position, expressed higher activities than GLA-27 and GLA-59, which carry the acyloxyacyl group at the 2-N-position. These results indicate that the acyl substituent (whether the counterpart of the C14-O-(C14) group is a C14 or a C14-OH group) and the binding position of the acyloxyacyl group at the 2-N- or the 3-O-position strongly influence the manifestation of antimicrobial and immunomodulating activities in different ways depending on the activity. Among the compounds, GLA-60 satisfied the structure requirements for protection against both VV and P. aeruginosa infections. This compound is a hopeful immunomodulator for prevention against broad microbial infections.
authors.affiliation: School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: M
authors.initials: M
authors.lastname: Matsuura
authors.forename: M
authors.initials: M
authors.lastname: Nakatsuka
authors.forename: J Y
authors.initials: JY
authors.lastname: Homma
authors.forename: M
authors.initials: M
authors.lastname: Kiso
authors.forename: A
authors.initials: A
authors.lastname: Hasegawa
authors.forename: C
authors.initials: C
authors.lastname: Nishimura
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D004351:Drug Resistance; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D011552:Pseudomonas Infections / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D014615:Vaccinia / Q000517:prevention & control*
chemical_list: D000276:Adjuvants, Immunologic; D008050:Lipid A; D005944:Glucosamine