Anti-herpes simplex virus activity of n-docosanol correlates with intracellular metabolic conversion of the drug.
The 22-carbon fatty alcohol, n-docosanol, exhibits in vitro antiviral activity against several lipid-enveloped viruses including herpes simplex viruses 1 and 2 by a mechanism that interferes with normal viral entry into target cells. We previously reported that mammalian cells incorporate significant quantities of radiolabeled n-docosanol. Herein, we report that cells extensively metabolize the internalized fatty alcohol. This is evidenced by incorporation of up to 60% of cell-associated radiolabel into phospholipids that copurify with phosphatidylcholine and phosphatidylethanolamine. Analysis by chemical (Vitride) reduction suggests that a significant portion of n-docosanol is oxidized to n-docosanoic acid and then incorporated as an acyl group on polar lipids. A measurable amount of radiolabel, however, is resistant to Vitride reduction, consistent with incorporation of n-docosanol into ether lipids. The rate and extent of metabolic conversion of n-docosanol vary with the cell type and surfactant used to suspend the compound. Furthermore, the anti-HSV activity of n-docosanol is quantitatively proportional to the amount of metabolism observed. These findings suggest that the anti-HSV activity of n-docosanol involves cellular uptake and metabolism of the drug.
LIDAK Pharmaceuticals, La Jolla, CA 92037, USA.
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D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001386:Azides / Q000494:pharmacology; D002250:Carbon Radioisotopes; D002417:Cattle; D002460:Cell Line; D002522:Chlorocebus aethiops; D002855:Chromatography, Thin Layer; D003847:Deoxyglucose / Q000494:pharmacology; D005233:Fatty Alcohols / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007668:Kidney; D007700:Kinetics; D009942:Organometallic Compounds; D018139:Simplexvirus / Q000187:drug effects*; D019810:Sodium Azide; D014709:Vero Cells / Q000378:metabolism
D000998:Antiviral Agents; D001386:Azides; D002250:Carbon Radioisotopes; D005233:Fatty Alcohols; D009942:Organometallic Compounds; C007396:dihydrobis(2-methoxyethoxy)aluminate; D019810:Sodium Azide; C529236:docosanol; D003847:Deoxyglucose