Efficacy of the acyclic guanosine analog buciclovir [(R)-9-(3,4-dihydroxybutyl)guanine] in experimental genital herpes

Abstract

The efficacy of the anti-herpesvirus drug buciclovir [(R)-9-(3,4-dihydroxybutyl)guanineI was investigated in guinea pigs and mice infected intravaginally with herpes simplex virus type 2. Topical treatment initiated early after infection was efficacious, in contrast to topical treatment delayed 24 h or more. Systemic treatment of infected mice could not prevent the spread of virus to the brain and mortality. Systemically administered buciclovir had an effect in guinea pigs, even after delayed onset of treatment, but this effect required high doses of the drug. Our results suggest that buciclovir has only a limited effect against herpesvirus infections once the virus is present in the nervous systems of infected animals.(R)-9-(3,4-Dihydroxybutyl)guanine (buciclovir [BCV]) is a new antiherpetic, acyclic guanosine analog (8). Phosphorylation of BCV by the thymidine kinases induced by herpes simplex virus type 1 (HSV-1) or HSV-2 determines in part the specificity of the drug, as BCV is a poor substrate for cellular kinases (8, 9; K. Stenberg, A. Larsson, and R. Datema, J. Biol. Chem., in press). In herpes simplex virusinfected cells BCV is rapidly phosphorylated to its triphosphate, a specific inhibitor of the viral DNA polymerases (Stenberg et al., in press). Thus, BCV resembles other antiherpetic acyclic guanosine analogs, such as 9-(2-hydroxyethoxymethyl)guanine (acyclovir [ACV]), 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine, and 9-(4-hydroxybutyl)guanine in its mechanism of action (for a review see reference 10).In cell cultures BCV and 9-(4-hydroxybutyl)guanine are approximately equally potent in inhibiting the replication of HSV-1 and HSV-2 (7, 8). However, only BCV shows potent antiviral effects in vivo (2). These results emphasize the importance of evaluating the antiherpetic guanosine analogs in vivo. In this study we evaluated the efficacy of BCV in experimental genital HSV-2 infections in guinea pigs and mice. MATERIALS AND METHODSMaterials. The acyclic guanosine analogs BCV and ACV were synthesized at Astra Lakemedel AB (manuscript in preparation). For topical use the drugs were suspended in the water-based cream used by Collins and Oliver (1) for ACV at concentrations of 5, 10, and 20% (wt/wt). The concentrations of BCV in serum were determined as previously described (2). The cream base without drug was used as placebo.Viruses. HSV-2 strain 91075 is a clinical isolate and was used in its third cell culture passage (2). HSV-2 strain MS was obtained from the American Type Culture Collection, Rockville, Md., and was propagated in Vero cells. The effects of BCV on replication of HSV-1 and HSV-2 in several cell lines have been described previously (2).Animals Female NMRI mice (Anticimex) weighing 15 g were used to study genital herpes simplex virus infections in mice. Each mouse was inoculated intravaginally with 7 x 104 PFU of HSV-2 strain MS or 2 x 104 PFU of HSV-2 strain 91075 by using a micropipette. Topical treatments were administered by applying one-half of the dose intravaginally and the other half ov...

Limited Efficacy of Inhibitors of Herpes Simplex Virus DNA Synthesis in Murine Models of Recrudescent Disease

“…Indeed, when BCV was given subcutaneously in high doses (2 × 400 mg/kg/day) a beneficial effect against zoster development was obtained if treatment was started 72 h p.i. (Lundgren et al, 1986; data not shown). Nevertheless, in these experiments a maximum of 50~ reduction in zoster score was obtained, and therefore this treatment was less efficacious than treatment started 48 h p.i., when virus had already reached the sensory ganglia but not yet the skin of the lower flank (see Simmons & Nash, 1984).…”

Electrochemical enantioselective dihydroxylation reaction of N-alkenyl nucleobases for the construction of chiral acyclic nucleosides

“…Chiral acyclic nucleosides have received considerable attention because of their appealing biological activities and their usage as therapeutic agents for the treatment of HIV and hepatitis. 1–5 For example, ( R )-buciclovir is a specific inhibitor of the viral DNA polymerases in herpes simplex virus infection 2 and ( S )-cidofovir has been approved as an injectable medication for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. 3 d -Eritadenine is a potent inhibitor of S -adenosyl- l -homocysteine hydrolase 4 (Fig.…”