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: Regina Cencic, Marc Desforges, David R Hall, Dima Kozakov, Yuhong Du, Jaeki Min, Raymond Dingledine, Haian Fu, Sandor Vajda, Pierre J Talbot, Jerry Pelletier
• Journal: Journal of virology (J Virol) Vol. 85 Issue 13 Pg. 6381-9 (Jul 2011) ISSN: 1098-5514 [Electronic] United States
• PMID: 21507972 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Eukaryotic Initiation Factor-4E
• Eukaryotic Initiation Factor-4G
• RNA Caps
• Small Molecule Libraries
• Viral Proteins

Topics

• Antiviral Agents (chemistry, pharmacology)
• Cell Line
• Coronavirus 229E, Human (drug effects, metabolism, pathogenicity, physiology)
• Drug Discovery
• Eukaryotic Initiation Factor-4E (antagonists & inhibitors, metabolism)
• Eukaryotic Initiation Factor-4G (antagonists & inhibitors, metabolism)
• High-Throughput Screening Assays
• Humans
• Protein Biosynthesis (drug effects)
• RNA Caps (genetics, metabolism)
• Small Molecule Libraries
• Viral Proteins (metabolism)
• Virus Replication (drug effects)