title: Blocking eIF4E-eIF4G interaction as a strategy to impair coronavirus replication.
abstract: Coronaviruses are a family of enveloped single-stranded positive-sense RNA viruses causing respiratory, enteric, and neurologic diseases in mammals and fowl. Human coronaviruses are recognized to cause up to a third of common colds and are suspected to be involved in enteric and neurologic diseases. Coronavirus replication involves the generation of nested subgenomic mRNAs (sgmRNAs) with a common capped 5' leader sequence. The translation of most of the sgmRNAs is thought to be cap dependent and displays a requirement for eukaryotic initiation factor 4F (eIF4F), a heterotrimeric complex needed for the recruitment of 40S ribosomes. We recently reported on an ultrahigh-throughput screen to discover compounds that inhibit eIF4F activity by blocking the interaction of two of its subunits (R. Cencic et al., Proc. Natl. Acad. Sci. U. S. A. 108:1046-1051, 2011). Herein we describe a molecule from this screen that prevents the interaction between eIF4E (the cap-binding protein) and eIF4G (a large scaffolding protein), inhibiting cap-dependent translation. This inhibitor significantly decreased human coronavirus 229E (HCoV-229E) replication, reducing the percentage of infected cells and intra- and extracellular infectious virus titers. Our results support the strategy of targeting the eIF4F complex to block coronavirus infection.
authors.affiliation: McIntyre Medical Sciences Building, Rm. 810, 3655 Promenade Sir William Osler, McGill University, Montreal, Quebec, Canada H3G 1Y6.
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.forename: Marc
authors.initials: M
authors.lastname: Desforges
authors.forename: David R
authors.initials: DR
authors.lastname: Hall
authors.forename: Dima
authors.initials: D
authors.lastname: Kozakov
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.forename: Raymond
authors.initials: R
authors.lastname: Dingledine
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: Sandor
authors.initials: S
authors.lastname: Vajda
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Talbot
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D028941:Coronavirus 229E, Human / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D055808:Drug Discovery; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors* / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D014176:Protein Biosynthesis / Q000187:drug effects; D012315:RNA Caps / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D012315:RNA Caps; D054852:Small Molecule Libraries; D014764:Viral Proteins