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.

Comparative Proteome Analysis of Porcine Jejunum Tissues in Response to a Virulent Strain of Porcine Epidemic Diarrhea Virus and Its Attenuated Strain

“…Alterations of factors involved in viral transcription and translation may affect viral replication. Coronavirus replication involves the generation of nested subgenomic mRNAs (sgmRNAs) with a common capped 5′ leader sequence [51]. To organize optical transcription of sgmRNAs, its 5′ terminal leader sequences need to interact with intergenic (IG) sequences just upstream of each open reading frame (ORF).…”

“…The translation of most of the sgmRNAs requires eukaryotic initiation factor 4F (eIF4F), which is composed of eIF4A, eIF4E, and eIF4G. Regina Cencic et al have reported that replication of human coronavirus 229E was significantly inhibited by blocking the interaction between eIF4E and eIF4G [51]. In the case of vesicular stomatitis virus and influenza virus, viral replication was also inhibited by silencing eIF4G1 [54,55].…”

Receptor tyrosine kinase inhibitors block proliferation of TGEV mainly through p38 mitogen-activated protein kinase pathways

“…In MHV, p38 MAPK activation results in the phosphorylation of eIF4E, which facilitates virus protein synthesis and the subsequent production of infectious virus (Banerjee et al, 2002). Cencic et al reported that targeting the eIF4F complex is a strategy for blocking CoV infection (Cencic et al, 2011). eIF4E is a downstream molecule of p38 MAPK and Fig.…”

Therapeutic interventions to disrupt the protein synthetic machinery in melanoma

“…4EGI‐1 inhibited xenograft melanoma and breast cancer tumor growth with negligible toxicity (Chen et al., ). 4E1RCat is a molecule identified in a screen to bind to eIF4G to hinder eIF4F assembly (Cencic et al., ), and 4E2RCat was identified to prevent eIF4E interaction with eIF4G (Cencic et al., ). Both inhibit cap‐dependent translation and reverse drug resistance in a lymphoma model, but neither molecule has been studied in melanoma.…”