Dimeric Bisbenzimidazole DB₂A(7) Protects Mice From Lethal Genital Herpes and Herpetic Skin Lesions

Herpes simplex virus type 1 (HSV-1) is among the most common pathogens in the human population. Primary infection and reactivation of the virus can cause serious diseases and death. The drug resistance to all approved anti-HSV agents poses a significant challenge, especially for immunocompromised patients. This study focuses on some details of the dimeric bisbenzimidazole DB₂A(7) synthesis and its antiviral properties of against both HSV-1 sensitive and resistant acyclovir isolates. Optimization of the synthesis of DB₂A(7) resulted in an increase in the total yield from 20% to 44%, reduction of labor intensity and removal of highly toxic and carcinogenic hydrazine. The DB₂A(7) binding to thymus DNA was confirmed by a combination of physicochemical methods including calculation of the binding constant. DB₂A(7) demonstrated the in vitro capacity to inhibit viral activity, both before and after cell infection, and effectively inactivated cell-free viruses. Gene expression analysis by RT-PCR revealed a significant reduction in the transcription of the gene encoding the immediate early ICP0 HSV-1 protein, suggesting a mechanism of action different from that of acyclovir. We first demonstrated the in vivo preventive effect of DB₂A(7) towards lethal skin HSV-1 infection in mice as well as its capacity to protect animals from lethal genital herpes. The data obtained implied the potential of the synthesized DB₂A(7) as a new antiviral agent against the lethal HSV-1 infection.