Cellular Targets for the Treatment of Flavivirus Infections

Abstract

Classical antiviral therapy targets viral functions, mostly viral enzymes or receptors. Successful examples include precursor herpesvirus drugs, antiretroviral drugs that target reverse transcriptase and protease, influenza virus directed compounds as well as more recent direct antiviral agents (DAA) applied in the treatment of hepatitis C virus (HCV). However, from early times, the possibility of targeting the host cell to contain the infection has frequently re-emerged as an alternative and complementary antiviral strategy. Advantages of this approach include an increased threshold to the emergence of resistance and the possibility to target multiple viruses. Major pitfalls are related to important cellular side effects and cytotoxicity. In this mini-review, the concept of host directed antiviral therapy will be discussed with a focus on the most recent advances in the field of Flaviviruses, a family of important human pathogens for which we do not have antivirals available in the clinics.

Keywords: antiviral; flavivirus; host-directed therapy; mechanism of action; screening tools.

Figure 1

Strategies for antiviral HDT. (Top-Down) approaches consider drugs from various sources as starting material for a screen of antiviral activity. These approaches can identify drugs with both viral and cellular targets. However, when starting from complex mixtures, it is not easy to define the active compound, while screenings of Food and Drug Administration (FDA) registered drugs have the advantage of knowing the drug in advance and, in most cases, the target. Bottom-up approaches are based on unbiased screens by depleting or overexpressing host factors or miRNAs. Here the critical issue is to find the drug for the target that is identified by the screen. (Bottom-Up) approaches also include various approaches where the network of virus-host interactions is studied or where the response of the cell to the infection is analyzed as a whole. These methods require functional validation and only after that it is possible to proceed further and select the drugs.