Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice

Antiviral Res. 2018 Jan;149:41-47. doi: 10.1016/j.antiviral.2017.11.008. Epub 2017 Nov 10.

Abstract

Chronic hepatitis B virus infection cannot be cured by current therapies, so new treatments are urgently needed. We recently identified novel inhibitors of the hepatitis B virus ribonuclease H that suppress viral replication in cell culture. Here, we employed immunodeficient FRG KO mice whose livers had been engrafted with primary human hepatocytes to ask whether ribonuclease H inhibitors can suppress hepatitis B virus replication in vivo. Humanized FRG KO mice infected with hepatitis B virus were treated for two weeks with the ribonuclease H inhibitors #110, an α-hydroxytropolone, and #208, an N-hydroxypyridinedione. Hepatitis B virus viral titers and S and e antigen plasma levels were measured. Treatment with #110 and #208 caused significant reductions in plasma viremia without affecting hepatitis B virus S or e antigen levels, and viral titers rebounded following treatment cessation. This is the expected pattern for inhibitors of viral DNA synthesis. Compound #208 suppressed viral titers of both hepatitis B virus genotype A and C isolates. These data indicate that Hepatitis B virus replication can be suppressed during infection in an animal by inhibiting the viral ribonuclease H, validating the ribonuclease H as a novel target for antiviral drug development.

Keywords: Antivirals; Chimeric mice; FRG; HBV; RNaseH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • DNA Replication / drug effects
  • Genotype
  • Hepatitis B / drug therapy
  • Hepatitis B / virology
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / physiology*
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Pilot Projects
  • Ribonuclease H / antagonists & inhibitors*
  • Treatment Outcome
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Ribonuclease H