LAUSR

ABSTRACT Pritelivir, a helicase‐primase inhibitor, has excellent in vitro and in vivo activity against human herpes simplex virus (HSV). Mice lethally infected with HSV type 1 or 2, including acyclovir‐resistant strains, were treated 72 h after infection for 7 days with pritelivir or acyclovir. Both drugs were administered orally twice daily either alone or in combination. Dosages of pritelivir from 0.3 to 30 mg/kg reduced mortality (P < 0.001) against HSV‐1, E‐377. With an acyclovir resistant HSV‐1, 11360, pritelivir at 1 and 3 mg/kg increased survival (P < 0.005). With HSV‐2, MS infected mice, all dosages higher than the 0.3 mg/kg dose of pritelivir were effective (P < 0.005). For acyclovir resistant HSV‐2, strain 12247, pritelivir dosages of 1–3 mg/kg significantly improved survival (P < 0.0001). Combination therapies of pritelivir at 0.1 or 0.3 mg/kg/dose with acyclovir (10 mg/kg/dose) were protective (P < 0.0001) when compared to the vehicle treated group against HSV‐2, strain MS (in line with previous data using HSV‐1). An increased mean days to death (P < 0.05) was also observed and was indicative of a potential synergy. Pharmacokinetic studies were performed to determine pritelivir concentrations and a dose dependent relationship was found in both plasma and brain samples regardless of infection status or time of initiation of dosing. In summary, pritelivir was shown to be active when treatment was delayed to 72 h post viral inoculation and appeared to synergistically inhibit mortality in this model in combination with acyclovir. We conclude pritelivir has potent and resistance‐breaking antiviral efficacy with potential for the treatment of potentially life‐threatening HSV type 1 and 2 infections, including herpes simplex encephalitis. HighlightsPritelivir, a HSV helicase‐primase inhibitor, was shown to be active in an murine model of herpes simplex encephalitis.Treatment was efficacious even when onset was delayed to 72 h post infection with sensitive or acyclovir resistant HSV.Combination therapy with acyclovir indicated an additive (potentially synergistic) effect on drug sensitive HSV.Pritelivir crossed the blood/brain barrier with comparable exposures in HSV infected and uninfected animals.Pritelivir could be a useful treatment option for herpes simplex encephalitis.