Novel inhibitors of HSV-1 protease effective in vitro and in vivo
Magdalena Pachota, Renata Grzywa, Jakub Iwanejko, Aleksandra Synowiec, Dominika Iwan, Karolina Kamińska, Marcin Skoreński, Ewa Bielecka, Krzysztof Szczubiałka, Maria Nowakowska, Cameron D. Mackereth, Elżbieta Wojaczyńska, Marcin Sieńczyk, Krzysztof Pyrć
Abstract
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.