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Stress granule-inducing eukaryotic translation initiation factor 4A inhibitors block influenza A virus replication

Patrick D. Slaine, Mariel Kleer, Nathan Smith, Denys A. Khaperskyy, View ORCID ProfileCraig McCormick
doi: https://doi.org/10.1101/194589
Patrick D. Slaine
1Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax NS, Canada B3H 4R2
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Mariel Kleer
1Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax NS, Canada B3H 4R2
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Nathan Smith
2Department of Community Health and Epidemiology, Dalhousie University, 5790 University Avenue, Halifax NS, Canada B3H 1V7
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Denys A. Khaperskyy
1Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax NS, Canada B3H 4R2
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  • For correspondence: d.khaperskyy@dal.ca craig.mccormick@dal.ca
Craig McCormick
1Department of Microbiology and Immunology, Dalhousie University, 5850 College Street, Halifax NS, Canada B3H 4R2
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  • ORCID record for Craig McCormick
  • For correspondence: d.khaperskyy@dal.ca craig.mccormick@dal.ca
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ABSTRACT

Eukaryotic translation initiation factor 4A (eIF4A) is a helicase that facilitates assembly of the translation preinitiation complex by unwinding structured mRNA 5’ untranslated regions. Pateamine A (PatA) and silvestrol are natural products that disrupt eIF4A function and arrest translation, thereby triggering the formation of cytoplasmic aggregates of stalled preinitiation complexes known as stress granules (SGs). Here we examined the effects of eIF4A inhibition by PatA and silvestrol on influenza A virus (IAV) protein synthesis and replication in cell culture. Treatment of infected cells with either PatA or silvestrol at early times post-infection results in SG formation, arrest of viral protein synthesis and failure to replicate the viral genome. PatA, which irreversibly binds to eIF4A, sustained long-term blockade of IAV replication following drug withdrawal, and inhibited IAV replication at concentrations that had minimal cytotoxicity. By contrast, the antiviral effects of silvestrol were fully reversible; drug withdrawal caused rapid SG dissolution and resumption of viral protein synthesis. IAV inhibition by silvestrol was invariably associated with cytotoxicity. PatA blocked replication of genetically divergent IAV strains, suggesting common dependence on host eIF4A activity. This study demonstrates the feasibility of targeting core host protein synthesis machinery to prevent viral replication.

IMPORTANCE Influenza A virus (IAV) relies on cellular protein synthesis to decode viral messenger RNAs. Pateamine A and silvestrol are natural products that inactivate an essential protein synthesis protein known as eIF4A. Here we show that IAV is sensitive to these eIF4A inhibitor drugs. Treatment of infected cells with pateamine A or silvestrol prevented synthesis of viral proteins, viral genome replication and release of infectious virions. The irreversible eIF4A inhibitor pateamine A sustained long-term blockade of viral replication, whereas viral protein synthesis quickly resumed after silvestrol was removed from infected cells. Prolonged incubation of either infected or uninfected cells with these drugs induced the programmed cell death cascade called apoptosis. Our findings suggest that core components of the host protein synthesis machinery are viable targets for antiviral drug discovery. The most promising drug candidates should selectively block protein synthesis in infected cells without perturbing bystander uninfected cells.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 02, 2017.
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Stress granule-inducing eukaryotic translation initiation factor 4A inhibitors block influenza A virus replication
Patrick D. Slaine, Mariel Kleer, Nathan Smith, Denys A. Khaperskyy, Craig McCormick
bioRxiv 194589; doi: https://doi.org/10.1101/194589
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Stress granule-inducing eukaryotic translation initiation factor 4A inhibitors block influenza A virus replication
Patrick D. Slaine, Mariel Kleer, Nathan Smith, Denys A. Khaperskyy, Craig McCormick
bioRxiv 194589; doi: https://doi.org/10.1101/194589

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