Inhibition of hepatitis C virus replication and internal ribosome entry site-dependent translation by an RNA molecule

J Gen Virol. 2009 Jul;90(Pt 7):1659-1669. doi: 10.1099/vir.0.008821-0. Epub 2009 Mar 4.

Abstract

Hepatitis C virus (HCV) protein synthesis is mediated by a highly conserved internal ribosome entry site (IRES), mostly located at the 5' untranslatable region (UTR) of the viral genome. The translation mechanism is different from that used by cellular cap-mRNAs, making IRESs an attractive target site for new antiviral drugs. The present work characterizes a chimeric RNA molecule (HH363-50) composed of two inhibitors: a hammerhead ribozyme targeting position 363 of the HCV genome and an aptamer directed towards the essential stem-loop structure in domain IV of the IRES region (which contains the translation start codon). The inhibitor RNA interferes with the formation of a translationally active complex, stalling its progression at the level of 80S particle formation. This action is likely related to the effective and specific blocking of HCV IRES-dependent translation achieved in Huh-7 cells. The inhibitor HH363-50 also reduces HCV RNA levels in a subgenomic replicon system. The present findings suggest that HH363-50 could be an effective anti-HCV compound and highlight the possibilities of antiviral agents based on RNA molecules.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Aptamers, Nucleotide / pharmacology
  • Base Sequence
  • Cell Line
  • Hepacivirus / drug effects*
  • Hepatocytes / virology
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • Protein Biosynthesis / drug effects*
  • RNA / pharmacology*
  • RNA, Catalytic / pharmacology
  • RNA, Viral / biosynthesis
  • Virus Replication / drug effects*

Substances

  • Antiviral Agents
  • Aptamers, Nucleotide
  • RNA, Catalytic
  • RNA, Viral
  • hammerhead ribozyme
  • RNA