Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation

RNA helicases are the largest group of enzymes in eukaryotic RNA metabolism. The DEXID/H-box putative RNA helicases form the helicase superfamily II, whose members are defined by seven highly conserved amino acid motifs, making specific targeting of selected members a challenging pharmacological problem. The translation initiation factor elF4A is the prototypical DEAD-box RNA helicase that works in conjunction with elF4B and eIF4H and as a subunit of elF4F to prepare the mRNA template for ribosome binding, possibly by unwinding the secondary structure proximal to the 5' m(7)GpppN cap structure. We report the identification and characterization of a small molecule inhibitor of eukaryotic translation initiation that acts in an unusual manner by stimulating elF4A-associated activities. Our results suggest that proper control of elF4A helicase activity is necessary for efficient ribosome binding and demonstrate the feasibility of selectively targeting DEAD-box RNA helicases with small molecules.