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1) DRUID project: Identification of antiviral targets in lipid metabolic pathways

The goal of the DRUID project is to investigate flavivirus-host interactions to identify novel targets for the development of innovative antiviral therapies.
Like all intracellular pathogens, flaviviruses depend on the host cell's metabolism for successful replication. In this project funded by the Loewe Center DRUID, we investigate the dependency of flaviviruses on cellular lipid metabolism in order to identify potential targets for antiviral therapies. Using RNAi and CRISPR, we specifically knockdown or knockout key enzymes of de novo fatty acid and cholesterol biosynthesis, phospholipid and neutral lipid metabolism, as well as enzymes involved in remodeling lipids and compare the replication of DENV, YFV, WNV, TBEV and ZIKV. Similarly, we are testing selected inhibitors of metabolic pathways for their antiviral properties. Since flaviviruses can trigger both neurological and visceral diseases depending on their tropism, we will validate our results in different human cell types. In order to facilitate the analysis of medium-throughput approaches, we are working on the establishment of luciferase-based reporter constructs for the flaviviruses we are investigating.
Within the DRUID consortium, we plan to synthesize and test inhibitors against identified target enzymes that play an essential role in virus infection, but for which no specific inhibitors are available. In this context, further collaborations are planned for testing various direct-acting antivirals.

Model of flavivirus replication. Immunofluorescence microscopy of cells infected with different flaviviruses; red: viral E protein; green: LDs. Scheme of the DRUID project.