Virtual Screening of Hepatitis B Virus Pre-Genomic RNA as a Novel Therapeutic Target

The global burden imposed by hepatitis B virus (HBV) infection necessitates the discovery and design of novel antiviral drugs to complement existing treatments. One attractive and underexploited therapeutic target is epsilon, an similar to 85-nucleotide (nt) cis-acting regulatory stem-loop RNA located at the 3 '- and 5 '-ends of the pre-genomic RNA (pgRNA). Binding of the 5 '-end epsilon to the viral polymerase protein (P) triggers two early events in HBV replication: pgRNA and P packaging and reverse transcription. Our recent solution nuclear magnetic resonance spectroscopy structure of epsilon permits structure-informed drug discovery efforts that are currently lacking for P. Here, we employ a virtual screen against epsilon using a Food and Drug Administration (FDA)-approved compound library, followed by in vitro binding assays. This approach revealed that the anti-hepatitis C virus drug Daclatasvir is a selective epsilon-targeting ligand. Additional molecular dynamics simulations demonstrated that Daclatasvir targets epsilon at its flexible 6-nt priming loop (PL) bulge and modulates its dynamics. Given the functional importance of the PL, our work supports the notion that targeting epsilon dynamics may be an effective anti-HBV therapeutic strategy.

Automated summary

Discovering and designing novel antiviral drugs is crucial to combat the global burden of hepatitis B virus (HBV) infection. This study focuses on epsilon, a cis-acting regulatory RNA located at the ends of the pre-genomic RNA, as a potential therapeutic target for HBV. By using the anti-hepatitis C virus drug Daclatasvir, the study demonstrates the effectiveness of targeting epsilon dynamics as an anti-HBV therapeutic strategy.