The Zika virus (ZIKV) belongs to the flavivirus and is a single stranded positive RNA arbovirus [[1], [3], [2]]. The virus has the characteristics of widespread, strong infectivity, high frequency of mutation, and difficult to prevent, all of which poses a great threat to social development and public health [4,5]. The clinical profile of ZIKV infection is highly variable, and although most patients develop mild to moderate symptoms, some develop severe neurological complications, such as Guillain-Barre syndrome [2,6,7]. Currently, there is still a lack of effective drugs to treat ZIKV infection, relying only based on symptomatic treatment to reduce the incidence of complications [6,8]. Therefore, there is an urgent to develop effective drugs to prevent or treat ZIKV.

Natural compounds are widely used to treat a variety of infectious and noninfectious diseases [5,9]. Among polyphenols constitute a class of compounds with strong anti-infection activity [[9], [10], [11]]. Theaflavins (TFs), a polyphenolic compound, represent the primary extract of red tea. This compound has a wide range of pharmacological activities, including antioxidant, antibacterial and anticancer. TFs can be divided into theaflavin (TF1), theaflavin-3-gallate (TF2a), theaflavin-3′-gallate (TF2b) and theaflavin-3,3′-digallate (TF3) according to their substitutions and positions [9,12,13].

It has been reported that TFs exhibit potent antiviral activity against hepatitis C virus (HCV), herpes simplex virus, influenza A virus (IAV), human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [9,12,14,15]. However, there is limited information regarding the activity of TFs against ZIKV infection.

In previous reports, theaflavin gallate has been identified as a flavonoid anti-ZIKV protease inhibitor and theaflavin can target D5 of ZIKV NS146 MTase to inhibit ZIKV infection [16,17]. In the present study, we have revealed that TF2b inhibits ZIKV replication in cells and significantly promotes the survival rate of lethal ZIKV-infected mice. Additionally, TF2b treatment suppresses the inflammatory response caused by ZIKV infection, suggesting that the compound exhibits a promising therapeutic effect in anti-ZIKV. These findings not only broaden the antiviral scope of TFs, but also provide a novel option strategy for the treatment of Zika virus infection.