title: The antiviral drug ribavirin does not mimic the 7-methylguanosine moiety of the mRNA cap structure in vitro.
abstract: The eukaryotic initiation factor eIF4E binds the mRNA 5' cap structure and has a central role during translational initiation. eIF4E and the mechanisms to control its activity have oncogenic properties and thus have become targets for anticancer drug development. A recent study (Kentsis et al. 2004) presented evidence that the antiviral nucleoside ribavirin and its phosphorylated derivatives were structural mimics of the mRNA cap, high-affinity ligands for eIF4E, and potent repressors of eIF4E-mediated cell transformation and tumor growth. Based on these findings, we tested ribavirin, ribavirin triphosphate (RTP), and the dinucleotide RpppG for their ability to inhibit translation in vitro. Surprisingly, the ribavirin-based compounds did not affect translation at concentrations where canonical cap analogs efficiently block cap-dependent translation. Using a set of reporter mRNAs that are translated via either cap-dependent or viral internal ribosome entry sites (IRES)-dependent initiation, we found that these ribavirin-containing compounds did inhibit translation at high (millimolar) concentrations, but there was no correlation of this inhibition with an eIF4E requirement for translation. The addition of a ribavirin-containing cap to mRNA did not stimulate translation. Fluorescence titration experiments with eIF4E and the nuclear cap-binding complex CBC indicated affinities for RTP and RpppG that were two to four orders of magnitude lower than those of m(7)GTP and m(7)GpppG. We conclude that, at least with respect to translation, ribavirin does not act in vitro as a functional mimic of the mRNA cap.
authors.affiliation: Molecular Genetics Program, Victor Chang Cardiac Research Institute, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: Belinda
authors.initials: B
authors.lastname: Westman
authors.forename: Lisa
authors.initials: L
authors.lastname: Beeren
authors.forename: Ewa
authors.initials: E
authors.lastname: Grudzien
authors.forename: Janusz
authors.initials: J
authors.lastname: Stepinski
authors.forename: Remigiusz
authors.initials: R
authors.lastname: Worch
authors.forename: Joanna
authors.initials: J
authors.lastname: Zuberek
authors.forename: Jacek
authors.initials: J
authors.lastname: Jemielity
authors.forename: Ryszard
authors.initials: R
authors.lastname: Stolarski
authors.forename: Edward
authors.initials: E
authors.lastname: Darzynkiewicz
authors.forename: Robert E
authors.initials: RE
authors.lastname: Rhoads
authors.forename: Thomas
authors.initials: T
authors.lastname: Preiss
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D066298:In Vitro Techniques; D015394:Molecular Structure; D014176:Protein Biosynthesis / Q000502:physiology*; D012315:RNA Caps / Q000737:chemistry*; D012333:RNA, Messenger / Q000378:metabolism*; D012015:Reference Standards; D012254:Ribavirin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D012315:RNA Caps; D012333:RNA, Messenger; D006151:Guanosine; C016578:7-methylguanosine; D012254:Ribavirin