Enhancement of nonspecific resistance to viral infection by chemically synthesized lipid A-subunit analogs with different backbone structures and acyl groups.
Protection against vaccinia virus infection and induction of interferon (IFN) were investigated in Propionibacterium acnes-primed mice following treatment with chemically synthesized lipid A-subunit derivatives. The antiviral activity was based on the reduction of numbers of tail lesions in mice injected intravenously with the test compounds 1 day before virus infection. GLA-27, a 4-O-phosphono-D-glucosamine carrying 3-O-tetradecanoyl (C14) and N-3-tetradecanoyloxytetradecanoyl [C14-O-(C14)] groups, offered significant antiviral activity. Chemical modifications at the C1 position of GLA-27, e.g. phosphorylation, replacement of OH by an SH, did not cause a significant change in antiviral activity. GLA-57 carrying an N-3-dodecanoyloxytetradecanoyl group showed stronger activity than GLA-27, but GLA-58 carrying an N-3-hexadecanoyloxytetradecanoyl group did not exhibit significant activity. GLA-59 carrying 3-O-3-hydroxytetradecanoyl and N-C14-O-(C14) groups was more active than GLA-27 and GLA-57. GLA-60 possessing the same fatty acid substituents as GLA-59 but in the reversed order was the most active of all compounds tested. This suggests that the nature and position of the acyl substituents are important for achieving the antiviral effects. The (R) isomers of GLA-59 and GLA-60 possessed stronger IFN-inducing activity than the (S) isomers, but no significant difference in antiviral activity was seen between the isomers.
Ikeda
S
S
School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Kumazawa
Y
Y
Nishimura
C
C
Nakatsuka
M
M
Homma
J Y
JY
Kiso
M
M
Hasegawa
A
A
D000818:Animals; D002460:Cell Line; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007372:Interferons / Q000096:biosynthesis*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D014615:Vaccinia / Q000276:immunology* / Q000517:prevention & control; D014616:Vaccinia virus / Q000254:growth & development / Q000276:immunology*; D010948:Viral Plaque Assay
D008050:Lipid A; D007372:Interferons