Article abstract
Nature Chemical Biology 2, 213 - 220 (2006)
Published online: 12 March 2006 | doi:10.1038/nchembio776
Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A
Marie-Eve Bordeleau1, Ayaka Mori2, Monika Oberer3, Lisa Lindqvist1, Louisa S Chard4, Tatsuo Higa2, Graham J Belsham4, Gerhard Wagner3, Junichi Tanaka2 & Jerry Pelletier1,5
Abstract
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.
- Department of Biochemistry, McIntyre Medical Sciences Building Rm. 810, 3655 Promenade Sir William Osler, McGill University, Montreal, Quebec H3G 1Y6, Canada.
- Department of Chemistry, Biology, and Marine Sciences, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan.
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
- Institute for Animal Health, Pirbright, Woking, Surrey GU24 0NF, UK.
- McGill Cancer Center, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Correspondence to: Jerry Pelletier1,5 e-mail: jerry.pelletier@mcgill.ca
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