Novel inhibitors of HSV-1 protease effective in vitro and in vivo

Herpes simplex virus type 1 (HSV-1) is a widespread human pathogen known to cause infections of diverse severity, ranging from mild ulceration of mucosal and dermal tissues to life-threatening viral encephalitis. In most cases, standard treatment with acyclovir is sufficient to manage the disease progression. However, the emergence of ACV-resistant strains drives the need for new therapeutics and molecular targets. HSV-1 VP24 is a protease indispensable for the assembly of mature virions and, as such, constitutes an interesting target for the therapy. In this study, we present novel compounds, KI207M and EWDI/39/55BF, that block the activity of VP24 protease and consequently inhibit HSV-1 infection in vitro and in vivo. The inhibitors were shown to prevent the egress of viral capsids from the cell nucleus and suppress the cell-to-cell spread of the infection. They were also proven effective against ACV-resistant HSV-1 strains. Considering their low toxicity and high antiviral potency, the novel VP24 inhibitors could provide an alternative for treating ACV-resistant infections or a drug to be used in combined, highly effective therapy.

Automated summary

Herpes simplex virus type 1 (HSV-1) is a common human pathogen causing infections of varying severity. This study discovered novel compounds that inhibit the activity of HSV-1 VP24 protease, effectively suppressing the infection in vitro and in vivo, including ACV-resistant strains. These inhibitors also prevent the nucleus egress of viral capsids and cell-to-cell spread. Due to their low toxicity and high antiviral potency, these VP24 inhibitors may serve as alternative therapeutics for ACV-resistant infections or be used in combination therapies.