Open AccessIn Vitro and In Vivo Activity, Tolerability, and Mechanism of Action of BX795 as an Antiviral against Herpes Simplex Virus 2 Genital Infection
Author(s) -
James Hopkins,
Tejabhiram Yadavalli,
Rahul Suryawanshi,
Farreh Qatanani,
Ipsita Volety,
Raghuram Koganti,
Aqsa Iqbal,
Deepak Shukla
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00245-20
Subject(s) - herpes simplex virus , virology , in vivo , tolerability , nucleoside analogue , in vitro , virus , nucleoside , mechanism of action , genital herpes , biology , simplexvirus , medicine , herpesviridae , pharmacology , viral disease , adverse effect , biochemistry , microbiology and biotechnology
Herpes simplex virus type 2 (HSV-2) causes recurrent lesions in the anogenital area that may be transmitted through sexual encounters. Nucleoside analogs, such as acyclovir (ACV), are currently prescribed clinically to curb this infection. However, 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 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.