Automated high-throughput image-based screen discovers members of the Akt serine/threonine kinase family as targets for treatment of HEV virus infection in vitro

Forty-four years after the discovery of Hepatitis E virus as the etiological agent of viral hepatitis in human, treatment options remain limited to the off-label use of the nucleoside-analog ribavirin (RBV) and pegylated interferon-α. Although these drugs have made HEV infections manageable for the majority of patients, a considerable number of patients are either not eligible for standard treatment or do not respond to currently available treatment options. To find alternative antiviral drugs against HEV infections we developed a simple and effective image-based high-throughput screening assay using subgenomic HEV reporter replicons of genotype 3 expressing a GFP gene as a marker for viral replication in hepatoma cells. By screening up to 9,500 compounds derived from FDA-approved drug-libraries and performing dose-response assays with 170 of the most promising compounds, we identified at least 5 compounds that markedly inhibit viral infection at low micromolar concentrations in hepatoma cells. Finally, infection experiments with the human-derived HEV-3 p6-FL and the wild-boar HEV-3 83-2 virus identified inhibitors of the serine/threonine kinase Akt as a potential treatment target of pan-HEV infection in vitro.

In conclusion, screening drug-repurposing libraries proved to be a versatile tool for identifying novel drugs against HEV infections, but most importantly, our results suggest that pan-Akt inhibitors may be promising therapeutic candidates for the treatment of HEV infections.

 

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Artikel online veröffentlicht:
18. Januar 2023