A synthetic derivative of houttuynoid B prevents cell entry of Zika virus

Zika virus (ZIKV) is a re-emerging virus belonging to the family of Flaviviridae, which contains several human pathogens. A great deal of attention came through the association of ZIKV infection with an increasing number of microcephaly cases in newborns during the 2016 outbreak in Brazil. Currently, no anti-viral drug or vaccine is available. Houttuynoids are a group of structurally related flavonoid glycosides that can be isolated from Houttuynia cordata belonging to the family of Sauraceae. Moreover, H. cordata was described to have an antiviral effect on herpes simplex virus type 1 (HSV-1), human immunodeficiency virus type 1 (HIV-1) and influenza A virus (Hayashi et al., 1995). In light of this, this study aimed to investigate a potential antiviral effect of the synthetic houttuynoids TK1023 and TK1024 (i.e. houttuynoid B) on two ZIKV isolates (Uganda and French Polynesia). A significant decrease in the amount of intra- and extracellular viral genomes as well as infectious viral particles was observed after treatment with the tetra-O-acetylated houttuynoid TK1023 independent from the analyzed virus isolate. In contrast, TK1024 (houttuynoid B) had no effect on ZIKV. Treatment with TK1023 significantly decreases the number of infected cells 24 h and 48 h after infection, as compared to the control. Analysis of the mode of action revealed that TK1023 neither affects the viral genome replication nor the production of viral proteins nor morphogenesis or release. Binding and entry assays showed that TK1023 interferes with the entry of the virus in the cell. Thereby, the spread of ZIKV infection is impaired as the infection of the individual cell is inhibited. These data indicate that for both analyzed virus isolates the spread of ZIKV infection can be impaired by the synthetic houttuynoid TK1023 due to an inhibition of the viral entry.