The anti-herpes simplex virus activity of n-docosanol includes inhibition of the viral entry process.
n-Docosanol-treated cells resist infection by a variety of lipid-enveloped viruses including the herpesviruses. Previous studies of the mechanism of action demonstrated that n-docosanol inhibits an event prior to the expression of intermediate early gene products but subsequent to HSV attachment. The studies reported here indicate that n-docosanol inhibits fusion of the HSV envelope with the plasma membrane. Evidence suggests that antiviral activity requires a time-dependent metabolic conversion of the compound. Cellular resistance to infection declines after removal of the drug with a t1/2 of approximately 3 h. Reduced expression of viral genes in n-docosanol-treated cells was confirmed by a 70% reduction in expression of a reporter gene regulated by a constitutive promoter inserted into the viral genome. Inhibited release in treated cells of virion-associated regulatory proteins--an immediate post entry event--was indicated by a 75% reduction in the expression of beta-galactosidase in target cells carrying a stably transfected lacZ gene under control of an HSV immediate--early promoter. Finally, the fusion-dependent dequenching of a lipophilic fluorescent probe, octadecyl rhodamine B chloride, inserted into the HSV envelope was significantly inhibited in treated cells. Inhibition of fusion between the plasma membrane and the HSV envelope, and the subsequent lack of replicative events, may be the predominant mechanism for the anti-HSV activity of n-docosanol.
Pope
L E
LE
LIDAK Pharmaceuticals, San Diego, CA 92121, USA.
Marcelletti
J F
JF
Katz
L R
LR
Lin
J Y
JY
Katz
D H
DH
Parish
M L
ML
Spear
P G
PG
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D002522:Chlorocebus aethiops; D006224:Cricetinae; D005233:Fatty Alcohols / Q000494:pharmacology*; D005456:Fluorescent Dyes; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008561:Membrane Fusion; D011991:Receptors, Virus / Q000378:metabolism; D012235:Rhodamines; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D001616:beta-Galactosidase / Q000096:biosynthesis
D000998:Antiviral Agents; D005233:Fatty Alcohols; D005456:Fluorescent Dyes; D011991:Receptors, Virus; D012235:Rhodamines; C529236:docosanol; D001616:beta-Galactosidase; C044542:octadecyl Rhodamine B chloride