Inhibition of Hepatitis E Virus Replication by Novel Inhibitor Targeting Methyltransferase

Hepatitis E Virus (HEV) is a quasi-enveloped virus having a single-stranded, positive-sense RNA genome (similar to 7.2 kb), flanked with a 5' methylated cap and a 3' polyadenylated tail. The HEV open reading frame 1 (ORF1) encodes a 186-kDa polyprotein speculated to get processed and produce Methyltransferase (MTase), one of the four essential replication enzymes. In this study, we report the identification of the MTase inhibitor, which may potentially deplete its enzymatic activity, thus causing the cessation of viral replication. Using in silico screening through docking, we identified ten putative compounds, which were tested for their anti-MTase activity. This resulted in the identification of 3-(4-Hydroxyphenyl)propionic acid (HPPA), with an IC50 value of 0.932 +/- 0.15 mu M, which could be perceived as an effective HEV inhibitor. Furthermore, the compound was tested for inhibition of HEV replication in the HEV culture system. The viral RNA copies were markedly decreased from similar to 3.2 x 10(6) in untreated cells to similar to 4.3 x 10(2.8) copies in 800 mu M HPPA treated cells. Therefore, we propose HPPA as a potential drug-like inhibitor against HEV-MTase, which would need further validation through in vivo analysis using animal models and the administration of Pharmacokinetic and Pharmacodynamic (PK/PD) studies.

Automated summary

This study reports the identification of a potential MTase inhibitor for Hepatitis E Virus (HEV) replication. The inhibitor showed effective anti-HEV activity and further in vivo analysis and PK/PD studies are needed to validate its potential as a drug-like inhibitor.