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

Author:

Olenginski, Lukasz T

Kasprzak, Wojciech K

Attionu, Solomon K

Shapiro, Bruce A

Dayie, Theodore K
Author Address

Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA., Bioinformatics and Computational Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., RNA Biology Laboratory, National Cancer Institute, Frederick, MD 21702, USA.,

Abstract:

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 e, an ~85-nucleotide (nt) cis-acting regulatory stem-loop RNA located at the 3 39;- and 5 39;-ends of the pre-genomic RNA (pgRNA). Binding of the 5 39;-end e 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 e permits structure-informed drug discovery efforts that are currently lacking for P. Here, we employ a virtual screen against e 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 e-targeting ligand. Additional molecular dynamics simulations demonstrated that Daclatasvir targets e 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 e dynamics may be an effective anti-HBV therapeutic strategy.

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