Ansari, S.; Sarmah, D. T.; Verma, R.; Chandrasekar, K.; Chatterjee, S.; Surjit, M.

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis in lower- and middle-income countries. HEV infection may lead to acute liver failure, chronic liver disease and high mortality in pregnant women. Antiviral therapy is not a standard treatment for HEV patients. Computational biology tools promise to revolutionize the antiviral drug discovery. Here, we analyzed the transcriptome data of HEV infected primary human hepatocyte (PHH)-cells through connectivity map database and applied control theory on functional network to identify antiviral targets against HEV. The above analyses predicted PKC{beta}, PKB/AKT and CK1{varepsilon} as potential antiviral targets against HEV. The antiviral function of PKB/AKT and CK1{varepsilon} was experimentally validated by using respective biochemical inhibitors in g3 (genotype 3)-HEV replicon and Huh7 cell-based model of g3 and g1-HEV infection. Further, knockdown of CK1{varepsilon} showed a similar effect. These data confirmed that CK1{varepsilon} is an antiviral target for HEV. At present, there are no FDA approved drugs targeting CK1{varepsilon}. Etravirine is an FDA approved non-nucleoside reverse transcriptase inhibitor drug, used for the treatment of Human immunodeficiency virus type 1 (HIV-1) infected patients. An in silico study predicted Etravirine to be a potent inhibitor of CK1{varepsilon}. Our experiments revealed potent antiviral activity of Etravirine against HEV, which was mediated via its ability to inhibit the activity of CK1{varepsilon}. Taken together, the current study demonstrates that PKB/AKT and CK1{varepsilon} are bonafide antiviral targets for HEV and paves the way for repurposing Etravirine for the treatment of HEV infected patients.