Blocking eIF4E-eIF4G interaction as a strategy to impair coronavirus replication.

Regina Cencic 1 Marc Desforges 2 David R Hall 3 Dima Kozakov 3 Yuhong Du 4 Jaeki Min 4 Raymond Dingledine 4 Haian Fu 4 Sandor Vajda 3 Pierre J Talbot 2 Jerry Pelletier 1, 5, *
* Corresponding author
1 Department of Biochemistry [Montréal]
2 INRS-IAF - Institut Armand Frappier
3 Department of Biomedical Engineering [Boston]
4 Emory Chemical Biology Discovery Center
5 GCRC - Goodman Cancer Research Center [Montréal]
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.
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Submitted on : Wednesday, August 8, 2012 - 5:24:09 PM
Last modification on : Thursday, February 7, 2019 - 5:24:00 PM

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Regina Cencic, Marc Desforges, David R Hall, Dima Kozakov, Yuhong Du, et al.. Blocking eIF4E-eIF4G interaction as a strategy to impair coronavirus replication.. Journal of Virology, American Society for Microbiology, 2011, 85 (13), pp.6381-9. ⟨10.1128/JVI.00078-11⟩. ⟨pasteur-00723277⟩

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