Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A

Research output: Contribution to journalJournal articleResearchpeer-review

  • Marie-Eve Bordeleau
  • Ayaka Mori
  • Monika Oberer
  • Lisa Lindqvist
  • Louisa S Chard
  • Tatsuo Higa
  • Belsham, Graham John
  • Gerhard Wagner
  • Junichi Tanaka
  • Jerry Pelletier

RNA helicases are molecular motors that are involved in virtually all aspects of RNA metabolism. Eukaryotic initiation factor (eIF) 4A is the prototypical member of the DEAD-box family of RNA helicases. It is thought to use energy from ATP hydrolysis to unwind mRNA structure and, in conjunction with other translation factors, it prepares mRNA templates for ribosome recruitment during translation initiation. In screening marine extracts for new eukaryotic translation initiation inhibitors, we identified the natural product hippuristanol. We show here that this compound is a selective and potent inhibitor of eIF4A RNA-binding activity that can be used to distinguish between eIF4A-dependent and -independent modes of translation initiation in vitro and in vivo. We also show that poliovirus replication is delayed when infected cells are exposed to hippuristanol. Our study demonstrates the feasibility of selectively targeting members of the DEAD-box helicase family with small-molecule inhibitors.

Original languageEnglish
JournalNature Chemical Biology
Issue number4
Pages (from-to)213-20
Number of pages8
Publication statusPublished - Apr 2006

    Research areas

  • Adenosine Triphosphate/chemistry, Cross-Linking Reagents/chemistry, Dose-Response Relationship, Drug, Escherichia coli/metabolism, Eukaryotic Initiation Factor-4A/chemistry, Humans, Hydrolysis, Magnetic Resonance Spectroscopy, Models, Genetic, Plasmids/metabolism, Poliovirus/genetics, Promoter Regions, Genetic, Protein Binding, Protein Biosynthesis, RNA/chemistry, RNA Helicases/chemistry, RNA, Messenger/metabolism, Recombinant Proteins/chemistry, Ribosomes/chemistry, Structure-Activity Relationship, Transfection

ID: 257919071