Abstract
The hepatitis E virus- (HEV-) helicase as a novel drug-target was evaluated. While cell culture model was used for mutational characterization of helicase, in silico protein modeling and virtual screening were employed to identify helicase inhibitors. None of the saturation mutant replicons significantly affected RNA replication. Notably, mutants encompassing the Walker motifs replicated as wild-type, showing indispensability of nucleotides conservation in viability compared to known criticality of amino acids. A 3D modeling of HEV-helicase and screening of a compound dataset identified ten most promising inhibitors with drug likeness, notably, JFD02650, RDR03130, and HTS11136 that interacted with Walker A residues Gly975, Gly978, Ser979, and Gly980. Our model building and virtual identification of novel helicase inhibitors warrant further studies towards developing anti-HEV drugs.
Highlights
The hepatitis E virus (HEV) is an emerging pathogen that causes acute hepatitis E in general and chronic infection in immunocompromised individuals [1, 2]
Based on in silico polyprotein sequence analysis of genetically-close viruses, methyltransferase (MeT/MTase), Y, papain-like cysteine protease (PCP), proline-rich hinge/hypervariable region (PPR/HVR), X, helicase, and RNA-dependent RNA polymerase (RdRp) domains had been proposed in HEV ORF1 [9]
The hepatitis E virus- (HEV-)hel with established activities, offers an attractive drug-target. In view of this and the available information, the present study further extends molecular analysis of the HEV-hel domain, including protein modeling and virtual screening of potential helicase inhibitors as future anti-HEV drug candidates
Summary
The hepatitis E virus (HEV) is an emerging pathogen that causes acute hepatitis E in general and chronic infection in immunocompromised individuals [1, 2]. The HEV-hel/NTPase sequences (HEV1-ORF1; a.a. 9601204) are mapped between X and RdRp domains [9] It belongs to superfamily 1 (SF1) helicases with signature motifs (I, Ia, II, III, IV, V, and VI) and is shown to have multiple enzymatic functions [20]. As a functional protein, when expressed in prokaryotic system, HEV-hel showed both NTPase and 5-3 RNA duplex unwinding activities that were abolished upon introducing mutations in the Walker motifs [21]. The HEV-hel with established activities, offers an attractive drug-target In view of this and the available information, the present study further extends molecular analysis of the HEV-hel domain, including protein modeling and virtual screening of potential helicase inhibitors as future anti-HEV drug candidates
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