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The flaviviruses dengue (DEN), yellow fever (YF), Japanese encephalitis (JE), West Nile (WN), and tickbome encephalitis (TBE) viruses are emerging or reemerging pathogens, and are classified as Category A-C priority pathogens. No effective therapy is currently available for clinical treatment of flavivirus infections. Here I present three developments toward flavivirus drug discovery. (1) Using reverse genetic systems of flavivirus, we h ave developed a set of high-throughput screening (HTS) assays. A luciferase reporler was engineered into a self-replicating subgenomic replicon (containing a deletion of viral structural genes) and into a full-length viral genome to monitor viral replication. Potential inhibitors could be identified through suppression of luciferase signals upon compound incubation.