Inhibition Of Human Herpes Simplex Virus By Mitoxantrone Dihydrochloride And Its Preliminary Mechanism

Herpes simplex virus type-1(HSV-1)and HSV-2 aremajor causes of oral-labial and urogenital lesions,respectively.Severe infections of HSV are associated with life-threatening diseases.There are some antiviral medications with activity against HSV-1 and HSV-2,however,the incidence of drug resistance is increasing.The aim of our study was to identify newanti-HSV compound(s)with potential use for drug development.We screened a chemical library of around 1000 compounds for inhibitors of HSV-1-induced cell death.This screen led to the identification of mitoxantrone dihydrochloride(MD)with potent protection against HSV-1-induced death of the infected cells.Interestingly,addition of ~3μM MD in both human and mouse cells resulted in a strong inhibition of HSV-1 titer.Treatment of MD showed remarkable reduction of GFP signal intensity in the cells infected with GFP-labeled HSV-1.Moreover,MD efficiently blocked the expression levels of both HSV-1 and HSV-2 proteins in various cells.Notably,MD significantly inhibited the expression of immediate-early gene ICP27,which is essential for the expression of early and late viral gene products.Consistently,transcriptional expression of genes regulating HSV replication such as UL5,UL9,UL29,UL30,UL42 and UL52 were significant reduced in the presence of MD.Our study revealed that MD has potent antiviral activity against both HSV-1 and HSV-2 through a direct or indirect inhibition of the essential immediate early gene ICP27.Therefore,MD has potential for use in the development of anti-HSV therapy.However,the precise mechanisms still require funher investigation.