Anti-herpesvirus activity of adenine arabinoside analogues in tissue culture and a genital infection of mice and guinea pigs

Abstract

Four analogues of adenine arabinoside (ara-A) were compared for activity against herpes simplex virus (HSV) in tissue culture and in a genital infection of mice and guinea pigs. These analogues, 5′-monophosphate (ara-AMP), 5′-valerate ester (ara-AV), 2′,3′-diacetate ester (ara-ADA), and 2′,3′,5′-triacetate ester (ara-ATA) have greater water and lipid solubility and resistance to deamination than ara-A. In mouse embryo fibroblast cells, similar viral inhibitory levels were noted with ara-A, AMP, and ara-AV, while ara-ADA and ara-ATA were 6–10 times less active. In mice infected intravaginally with HSV type 2 (HSV-2), intravaginal treatment with 10% concentrations of each of the compounds beginning 3 h after viral challenge, had no effect on infection rates, titers of virus in vaginal secretions, mortality rates or the mean day of death as compared with placebo-treated controls. In the HSV-2 genital infection of guinea pigs, treatment with 10% vaginal creams or placebo vehicle was initiated 6 or 24 h after viral inoculation. In animals treated at 6 h with ara-A, ara-AMP and ara-AV, there was complete inhibition of viral replication in the vaginal tract and development of external genital lesions. When treatment with these three drugs was delayed 24 h after infection, there was no effect on vaginal virus titers, but lesion severity was reduced by ara-A or ara-AMP therapy. Ara-ATA was ineffective whether begun at 6 or 24 h. The greater solubility in water and lipid as well as the resistance to deamination of ara-AMP and ara-AV did not appear to enhance their antiviral activity over that of ara-A. Additionally, ara-ADA and ara-ATA exhibited less activity both in tissue culture and in the experimental genital infections.