Abstract
The separate (+) and (−) enantiomers of the acyclic guanosine analogue 9-[4-hydroxy-2-(hydroxymethyl)-butyl]guanine (2HM-HBG) were tested for inhibition of varicella-zoster virus (VZV), herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2). In all cases the (−) enantiomer was the most active enantiomer. The (+) enantiomer was 10 times less active than the racemate against VZV and inactive against HSV-1 and -2.
The parent compound, 9-(4-hydroxybutyl)guanine, containing an unbranched side chain, was inactive against VZV, whereas substitution with a hydroxymethyl group at the 2 or 3 position of the side chain conferred anti-VZV activity. The effect of hydroxymethyl substitution may increase the recognition of the compound by the VZV thymidine kinase by increasing its similarity to the natural substrate thymidine. Further substitution of the side chain of the parent compound with oxygen, fluorine or hydroxyl groups did not confer antiviral activity against VZV.
Two VZV strains were isolated which could be grown in the presence of high concentrations of 2HM-HBG and which were also cross-resistant to other nucleoside analogues. These strains induced very little viral thymidine kinase activity in infected cells and thus were probably deficient for a functional thymidine kinase.
2HM-HBG exhibited a persistent antiviral effect even after the nucleoside was removed from the medium of VZV-infected cells, whereas acyclovir did not show this effect.