Systems pharmacology uncovers Janus functions of botanical drugs: activation of host defense system and inhibition of influenza virus replication

Abstract

Given the imminent threat of influenza pandemics and continuing emergence of new drug-resistant influenza virus strains, novel strategies for preventing and treating influenza disease are urgently needed. Herbal medicine, used for thousands of years in combinational therapies (Herb Formula), plays a significant role in stimulating the host immune system in vivo, and meanwhile, in fighting against the pandemic by directly inhibiting influenza virus in vitro. Such potential Janus functions may spark interest in therapeutic manipulation of virus diseases. Unfortunately, the molecular mechanism of the Janus functions of the medicinal herbs in the treatment of influenza remains unclear. In this work, to illustrate the therapeutic concept of Janus functions in the treatment of influenza, we have introduced a novel systems pharmacology model that integrates pharmacokinetic screening, targeting and network analysis of two representative herbs Lonicera japonica and Fructus Forsythiae that are efficient in the treatment of influenza, inflammation and other diseases. 50 Chemicals with favorable pharmacokinetic profiles have been identified for the two herbs, and the ligand-target network was constructed by complementing the literature-based experimental data deposited in DrugBank. The annotation of these chemicals was assigned using a novel drug targeting approach, and mapped to target-disease and drug-target-pathway networks. The overall data suggest that the medicinal herbs function by indirectly suppressing the virus proliferation via regulating the immune systems in hosts, and also, by directly inhibiting virus proliferation through targeting viral proteins essential for the viral life cycle. For the first time, we have demonstrated the mechanism of medicinal herbs in prevention and treatment of virus diseases via the Janus functions on a systematic level.

Fig. 1

C–Th network. A compound and a protein of human origin are connected to each other if the protein is a target of the compound. The triangles and circles, respectively, represent potential compounds and targets for both herbs Lonicera japonica (red) and Fructus Forsythiae (yellow), and the overlapped compounds and targets between two herbs are shown in cyan and purple, respectively.

Fig. 2

T–D network. T–D link was generated by mapping a target's terminology to relevant terms from the medical subject headings. In this way, a total of 219 disease terms (cyan squares) which can be organized into 20 categories (pink hexagons) according to MeSH were obtained. The colors of target nodes are the same as Fig. 2.

Fig. 3

C–Tv network. A compound and a protein of virus origin are connected to each other if the protein is a target of the compound. The node has the same color as Fig. 2.

Fig. 4

C–T–P network. The information about the pathways as defined by the KEGG was collected and then the T–P network was built by connecting the targets and their related signaling pathways. The C–T–P network was constructed by overlaying the C–T network onto T–P network. The colors of compound and target nodes are the same as Fig. 2, and the pathway node is represented as pink hexagon.