Effect of ASP2151, a herpesvirus helicase-primase inhibitor, in a guinea pig model of genital herpes

Abstract

ASP2151 is a herpesvirus helicase-primase inhibitor with antiviral activity against varicella zoster virus and herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Here, we examined the potency and efficacy of ASP2151 against HSV in vitro and in vivo. We found that ASP2151 was more potent in inhibiting the replication of HSV-1 and HSV-2 in Vero cells in the plaque reduction assay and had greater anti-HSV activity in a guinea pig model of genital herpes than did acyclovir and valacyclovir (VACV), respectively. Oral ASP2151 given from the day of infection reduced peak and overall disease scores in a dose-dependent manner, resulting in complete prevention of symptoms at the dose of 30 mg/kg. The 50% effective dose (ED(50)) values for ASP2151 and VACV were 0.37 and 68 mg/kg, respectively, indicating that ASP2151 was 184-fold more potent than VACV. When ASP2151 was administered after the onset of symptoms, the disease course of genital herpes was suppressed more effectively than by VACV, with a significant reduction in disease score observed one day after starting ASP2151 at 30 mg/kg, whereas the therapeutic effect of VACV was only evident three days after treatment at the highest dose tested (300 mg/kg). This indicated that ASP2151 possesses a faster onset of action and wider therapeutic time window than VACV. Further, virus shedding from the genital mucosa was significantly reduced with ASP2151 at 10 and 30 mg/kg but not with VACV, even at 300 mg/kg. Taken together, our present findings demonstrated the superior potency and efficacy of ASP2151 against HSV.

Figure 1

Molecular structure of ASP2151.

Figure 2

Efficacies of ASP2151 and VACV on genital herpes symptoms in a guinea pig model of HSV-2 infection. Guinea pigs vaginally infected with HSV-2 were orally administered placebo (closed square); ASP2151 at a dose of 0.3 (open triangle), 1 (closed triangle), 3 (open circle), 10 (closed circle), or 30 mg/kg (open square); or VACV at a dose of 30 (open triangle), 100 (closed triangle), or 300 mg/kg (open circle) twice daily from Days 0 to 4 post-infection. The mean disease scores for ASP2151- (a) or VACV-treated (b) groups were calculated and plotted against days post-infection; (c) and (d) represent the area under the disease score-time curve from Days 0 to 21 post-infection (AUC_Day0–21; score × day). Data are expressed as the mean + SE of 8-10 animals per group. * P < 0.05, compared with the placebo group (Dunnett’s multiple comparison test).

Figure 3

Therapeutic efficacies of ASP2151 and VACV on genital herpes symptoms in a guinea pig model of HSV-2 infection. Guinea pigs vaginally infected with HSV-2 were orally administered placebo (closed square); ASP2151 at a dose of 1 (open triangle), 3 (closed triangle), 10 (open circle), or 30 mg/kg (closed circle); or VACV at a dose of 30 (open triangle), 100 (closed triangle), or 300 mg/kg (open circle) twice daily from Days 4 to 9 post-infection. The mean disease scores for each ASP2151- (a) or VACV-treated (b) groups were calculated and plotted against days post-infection. * P < 0.05, compared with the placebo group (Dunnett’s multiple comparison test); (c) and (d) represent the area under the disease score-time curve from Days 0 to 9 post-infection. Data are expressed as the mean + SE of 10 animals per group. * P < 0.05, compared with the placebo group (Dunnett’s multiple comparison test). ^# P < 0.05, compared with the AUCs of valaciclovir 300 mg/kg treatment group (Tukey’s multiple comparison test).

Figure 4

Efficacies of ASP2151 and VACV on genital titers on Day 5 post-infection in a guinea pig model of HSV-2 infection. Each datum point represents the HSV-2 titer for each animal in the respective treatment groups (n = 14). The horizontal line of each group marks the median HSV-2 titer level with the viral titers indicated in parentheses. The horizontal dotted line represents the detection limit of the assay. P < 0.05, comparison with placebo was statistically analyzed using Steel’s multiple comparison test.