Effect of acyl substituents of synthetic lipid A-subunit analogues on their immunomodulating antiviral activity.
A chemically synthesized lipid A-subunit analogue, GLA-60, 2-deoxy-4-O-phosphono-2-[(3R)-3-hydroxytetradecanamido]-3-O-[(3R)- 3- tetradecanoyloxytetradecanoyl]-D-glucose, has many of the activities of endotoxin but has little toxicity. Then, compounds with various lengths of acyl side chain of the acyloxyacyl group at the 3-O position of GLA-60 were synthesized and evaluated for interferon (IFN)-inducing activity, natural killer (NK) cell activation and antiviral activity. The compounds with acyl side chains between C8 and C15 exhibited significant antiviral activity (inhibition of pox tail lesion formation in vaccinia virus-infected mice), serum IFN-inducing activity and NK cell activation. However, the compound carrying a C2 or a C16 acyl side chain did not exhibit these activities. The compounds with a C13 or C14 acyl side chain showed strong protective against herpes simplex virus type 1 in cyclophosphamide-immunosuppressed mice.
School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
S
S
Ikeda
C
C
Nishimura
M
M
Matsuura
J Y
JY
Homma
M
M
Kiso
A
A
Hasegawa
D000215:Acylation; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy / Q000401:mortality; D007372:Interferons / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects; D008050:Lipid A / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018139:Simplexvirus / Q000187:drug effects; D014615:Vaccinia / Q000188:drug therapy; D014616:Vaccinia virus / Q000187:drug effects
D000998:Antiviral Agents; D008050:Lipid A; C056260:GLA 60; D007372:Interferons