title: Translation of viral mRNAs that do not require eIF4E is blocked by the inhibitor 4EGI-1.
abstract: High throughput screening has rendered new inhibitors of eukaryotic protein synthesis. One such molecule, 4EGI-1 has been reported to selectively block the initiation factor eIF4E. We have investigated the action of this inhibitor on translation directed by several viral mRNAs which, in principle, do not utilize eIF4E. We found that 4EGI-1 inhibits translation directed by poliovirus IRES, in rabbit reticulocyte lysates, to a similar extent as capped mRNA. Moreover, 4EGI-1 inhibits translation driven by poliovirus IRES, both in vitro and in cultured cells, despite cleavage of eIF4G by picornavirus proteases. Finally, translation of vesicular stomatitis virus mRNAs and Sindbis virus subgenomic mRNA is blocked by 4EGI-1 in infected cells to a similar extent as cellular mRNAs. These findings cast doubt on the selective action of this inhibitor, and suggest that this molecule may affect other steps in protein synthesis unrelated to cap recognition by eIF4E.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), c/Nicolás Cabrera, 1 Universidad Autónoma de Madrid, Cantoblanco 28049, Madrid, Spain. nsevillano@cbm.uam.es
authors.forename: Natalia
authors.initials: N
authors.lastname: Redondo
authors.forename: Manuel
authors.initials: M
authors.lastname: García-Moreno
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Sanz
authors.forename: Luis
authors.initials: L
authors.lastname: Carrasco
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002474:Cell-Free System; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006835:Hydrazones; D009574:Nitro Compounds / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D012328:RNA Viruses / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism*; D012367:RNA, Viral / Q000378:metabolism; D011817:Rabbits; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C517852:4EGI-1 compound; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D006835:Hydrazones; D009574:Nitro Compounds; D012333:RNA, Messenger; D012367:RNA, Viral; D013844:Thiazoles
keywords: 4EGI-1; IRES inhibitors; IRES translation; Picornavirus translation; eIF4E