Antiviral efficacy of the helicase-primase inhibitor amenamevir in murine models of severe herpesvirus infection

Abstract

Existing treatments have limited efficacy against severe infection associated with herpes simplex virus (HSV) and herpes zoster virus (VZV), particularly in immunocompromized patients and those with multidermatomal infection. This issue, along with issues regarding drug resistance, support the need for improved therapeutic options. To investigate the antiviral effect of amenamevir, a VZV and HSV helicase-primase inhibitor, in severe infection conditions, mouse models of severe HSV-1 infection were developed by immunosuppression or multidermatomal infection. Mice with cyclosporin-induced immunosuppression and HSV-1 infection via inoculation of a dorsolateral area of skin were orally treated with amenamevir (10–100 mg/kg/day) for different durations (2–5 days). Immunosuppressed mice maintained high skin HSV-1 titers in the absence of treatment. Amenamevir successfully reduced HSV-1 titers at all tested doses in immunosuppressed mice, but required a longer treatment period to avoid a rebound in viral titers due to immunosuppression. To compare the efficacy of amenamevir and valacyclovir, a murine model of multidermatomal HSV-1 infection was generated by scarifying the dorsolateral area of skin in a line and inoculating broadly with HSV-1. The mice were treated with amenamevir or valacyclovir starting on Day 3, 4, or 5 post-infection for 5 days. Although both drugs similarly reduced disease scores when treatment was started on Day 3, amenamevir also reduced disease severity when treatment was initiated on Day 4, whereas valacyclovir did not. Amenamevir was not affected by the host’s immune status in terms of effective oral doses and was more efficacious in treating severe cutaneous infection even when treatment initiation was delayed.