Herpes simplex virus type 1 (HSV-1) is a ubiquitous and widespread human pathogen, which gives rise to a range of diseases, including cold sores, corneal blindness, and encephalitis. Currently, the use of nucleoside analogs, such as acyclovir and penciclovir, in treating HSV-1 infection often presents limitation due to their side effects and low efficacy for drug-resistance strains. Therefore, new anti-herpetic drugs and strategies should be urgently developed. Here, we reported that baicalein, a naturally derived compound widely used in Asian countries, strongly inhibited HSV-1 replication in several models. Baicalein was effective against the replication of both HSV-1/F and HSV-1/Blue (an acyclovir-resistant strain) in vitro. In the ocular inoculation mice model, baicalein markedly reduced in vivo HSV-1/F replication, receded inflammatory storm and attenuated histological changes in the cornea. Consistently, baicalein was found to reduce the mortality of mice, viral loads both in nose and trigeminal ganglia in HSV-1 intranasal infection model. Moreover, an ex vivo HSV-1-EGFP infection model established in isolated murine epidermal sheets confirmed that baicalein suppressed HSV-1 replication. Further investigations unraveled that dual mechanisms, inactivating viral particles and inhibiting IκB kinase beta (IKK-β) phosphorylation, were involved in the anti-HSV-1 effect of baicalein. Collectively, our findings identified baicalein as a promising therapy candidate against the infection of HSV-1, especially acyclovir-resistant strain.
Keywords: Anti-HSV-1; Baicalein; CC50, 50% cytotoxic concentration; DCFH-DA, 2′,7′-dichlorofluorescin diacetate; EC50, 50% effective concentration; GB, glycoprotein B; HSV-1 infection; HSV-1, herpes simplex virus types 1; ICP, infected cell polypeptide; IKK-β phosphorylation; IKK-β, IκB kinase beta; IL-1β, interleukin 1 beta; IL-6, interleukin 6; IκB-α, inhibitor of NF-κB alpha; LPS, lipopolysaccharides; MOI, multiplicity of infection; NAC, N-acetyl-l-cysteine; NF-κB activation; NF-κB, nuclear factor kappa-B; PFU, plaque-forming units; PGA1, prostaglandin A1; ROS, reactive oxygen species; SI, selectivity index; TG, trigeminal ganglia; TNF-α, tumor necrosis factor alpha; Viral inactivation; dpi, days post-infection; p-IKK-β, phosphorylated-IKK beta; p-IκB-α, phosphorylated-IκB alpha.
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