In Vitro and In Vivo Activity, Tolerability and Mechanism of Action of BX795 as an Antiviral Against Herpes Simplex Virus-2 Genital Infection

Antimicrob Agents Chemother. 2020 Jun 29;AAC.00245-20. doi: 10.1128/AAC.00245-20. Online ahead of print.

Abstract

Herpes simplex virus type 2 (HSV-2) causes recurrent lesions in the ano-genital area that may be transmitted through sexual encounters. Nucleoside analogs such as acyclovir (ACV) are currently prescribed clinically to curb this infection. But in some cases, reduced efficacy has been observed due to the emergence of resistance against these drugs. In our previous study, we reported the discovery of a novel anti-HSV-1 small molecule, BX795 which was originally used as an inhibitor of TANK-binding kinase 1 (TBK1). In this study, we report the antiviral efficacy of BX795 on HSV-2 infection in vaginal epithelial cells in vitro at 10 μM and in vivo at 50 μM. Additionally, through biochemical assays in vitro and histopathology in vivo, we show the tolerability of BX795 in vaginal epithelial cells at concentrations as high as 80 μM. Our investigations also revealed that the mechanism of action of BX795's antiviral activity stems from the reduction of viral protein translation via inhibition of protein kinase B phosphorylation. Finally, using a murine model of vaginal infection, we show that topical therapy using 50 μM BX795 is well tolerated and efficacious in controlling HSV-2 replication.