Antiviral Activity against VZV and HSV Type 1 and Type 2 of the (+) and (−) Enantiomers of (R,S)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine, in Comparison to other Closely Related Acyclic Nucleosides

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.

Inhibition of SIV and HIV-2 Replication in Cynomolgus Monkeys by (-)9-[4-Hydroxy-2-(Hydroxymethyl)-Butyl]Guanine (H2G)

“…The (+)enantiomer of H2G at 3x10 mg kg-1 day-1 did not show any inhibition of SIV sm replication in monkeys (Fig. 2a) in agreement with the earlier observation that the (-)enantiomer was more inhibitory than the (+)enantiomer to HSV, VZV (Abele et al, 1991) and HHV-6 replication (Akesson- Johansson et al, 1990). The enantiomeric mixture (±)H2G at 3x25 mg kg-1 day-1 was inhibitory (Fig.…”

“…It was also observed that H2G and (±)H2G were not active against thymidine kinase negative HSV or VZV variants (Larsson et al, 1986;Abele et al, 1991). Surprisingly, in view of the fact that lentiviruses lack viral thymidine kinase, variable antiviral effect at 2->100 IlM of H2G and (±)H2G was found in different cells infected with HIV-1, HIV-2 and SIV sm' The variability was seen in all types of cells and for all viruses tested when the assays were repeated several times.…”

Selection and Characterization of Varicella-Zoster Virus Variants Resistant to ( R )-9-[4-Hydroxy-2-(Hydroxymethy)Butyl]Guanine

“…H2G showed a potency similar to that of ACV against HSV-1, but less potency against HSV-2. Previous studies done on TK-deficient VZV strains indicated that a functional viral TK was necessary in order to achieve the potent antiviral effect seen with H2G in vitro (1). In this study, we tested a TK-deficient HSV-1 mutant, HSV-1(F)⌬305, which has a genetically engineered deletion in the viral TK gene (21).…”

“…(R)-9-[4-Hydroxy-2-(hydroxymethy)butyl]guanine (H2G; USAN, omaciclovir) is a nucleoside analog with in vitro inhibitory activity against VZV, herpes simplex virus types 1 and 2 (HSV-1 and -2), Epstein-Barr virus, and human herpesvirus 6 (1,4,5,15). It is more active against VZV than the currently approved agents, ACV and penciclovir (PCV) (1,5,15).…”

“…It is more active against VZV than the currently approved agents, ACV and penciclovir (PCV) (1,5,15). H2G is also efficacious in simian varicella virus-infected monkeys, currently the best model for predicting efficacy against VZVrelated disease in humans (23).…”