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.

1型单纯疱疹病毒（HSV-1）是一种普遍存在的人类病原体，会引起一系列疾病，包括唇疱疹，角膜盲和脑炎。目前，由于诸如阿昔洛韦和喷昔洛韦之类的核苷类似物在治疗HSV-1感染中的应用，由于其副作用和对耐药菌株的低效作用，常常受到限制。因此，应紧急开发新的抗疱疹药物和策略。在这里，我们报道了黄ical素（一种在亚洲国家广泛使用的天然来源的化合物）在几种模型中强烈抑制了HSV-1复制。黄ical素在体外对HSV-1 / F和HSV-1 / Blue（抗阿昔洛韦的菌株）的复制均有效。在眼接种小鼠模型中，黄ical素明显减少体内HSV-1 / F复制，消退的炎性风暴和减弱的角膜组织学变化。一致地，在HSV-1鼻内感染模型中，发现黄ical素可降低小鼠的死亡率，降低鼻子和三叉神经节的病毒载量。此外，在分离的鼠表皮片中建立的离体HSV-1-EGFP感染模型证实黄ical素能抑制HSV-1复制。进一步的研究揭示了双重机制，即灭活病毒颗粒和抑制IκB激酶β（IKK- β）磷酸化，参与了黄ical素的抗HSV-1效应。总的来说，我们的发现确定黄ical素是抗HSV-1感染，特别是抗阿昔洛韦菌株的有前途的候选疗法。