Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

Abstract

Infections with flaviviruses, such as dengue, West Nile virus and the recently re-emerging Zika virus, are an increasing and probably lasting global risk. This Review summarizes and comments on the opportunities for broad-spectrum agents that are active against multiple flaviviruses. Broad-spectrum activity is particularly desirable to prepare for the next flaviviral epidemic, which could emerge from as-yet unknown or neglected viruses. Potential molecular targets for broad-spectrum antiflaviviral compounds include viral proteins, such as the viral protease or polymerase, and host targets that are exploited by these viruses during entry and replication, including α-glucosidase and proteins involved in nucleoside biosynthesis. Numerous compounds with broad-spectrum antiviral activity have already been identified by target-specific or phenotypic assays. For other compounds, broad-spectrum activity can be anticipated because of their mode of action and molecular targets.

Figure 1

Replication cycle and polyprotein organization of flaviviruses. A number of putative host cell receptors for flaviviruses is indicated at the cellular membrane, with significant evidence indicating the importance of DC-SIGN. The insert in the lower left corner shows the sequential and structural organization of the flaviviral polyprotein at the endoplasmic reticulum membrane, with the cleavage sites of the host and viral proteases. Note the color coding of the viral proteins, indicated at the bottom. C – capsid protein, prM – membrane protein, E – envelope protein, NS1, NS2, NS3, NS4, NS5 – nonstructural proteins 1–5.

Figure 2

Compounds acting at viral targets.

Figure 3

Compounds acting at host targets.

Figure 4

Compounds with other and unknown mechanisms of action.