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Small Molecule Targeting IRES Domain Inhibits Enterovirus 71 Replication via an Allosteric Mechanism that Stabilizes a Ternary Complex

Jesse Davila-Calderon, View ORCID ProfileNeeraj Patwardhan, Liang-Yuan Chiu, Andrew Sugarman, View ORCID ProfileZhengguo Cai, Srinivasa R. Penutmutchu, Mei-Ling Li, Gary Brewer, View ORCID ProfileAmanda E. Hargrove, Blanton S. Tolbert
doi: https://doi.org/10.1101/2020.03.10.981167
Jesse Davila-Calderon
1Department of Chemistry, Case Western Reserve University, Cleveland, OH
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Neeraj Patwardhan
2Department of Chemistry, Duke University, Durham, NC
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Liang-Yuan Chiu
1Department of Chemistry, Case Western Reserve University, Cleveland, OH
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Andrew Sugarman
1Department of Chemistry, Case Western Reserve University, Cleveland, OH
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Zhengguo Cai
2Department of Chemistry, Duke University, Durham, NC
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Srinivasa R. Penutmutchu
1Department of Chemistry, Case Western Reserve University, Cleveland, OH
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Mei-Ling Li
3Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ
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Gary Brewer
3Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ
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  • For correspondence: blanton.tolbert@case.edu amanda.hargrove@duke.edu brewerga@rwjms.rutgers.edu
Amanda E. Hargrove
2Department of Chemistry, Duke University, Durham, NC
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  • For correspondence: blanton.tolbert@case.edu amanda.hargrove@duke.edu brewerga@rwjms.rutgers.edu
Blanton S. Tolbert
1Department of Chemistry, Case Western Reserve University, Cleveland, OH
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  • For correspondence: blanton.tolbert@case.edu amanda.hargrove@duke.edu brewerga@rwjms.rutgers.edu
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Abstract

We herein report an RNA-targeting antiviral small molecule that reduces replication of the human enterovirus 71 (EV71) via stabilization of an inhibitory small molecule-RNA-protein ternary complex. The EV71 virus poses serious threats to human health, particularly in regions of Southeast Asia, and no FDA approved drugs or vaccines are available. We first screened an RNA-biased small molecule library using a peptide-displacement assay to identify ligands for the stem loop II structure of the EV71 internal ribosomal entry site, which was previously shown to impact viral translation and replication. One ligand, DMA-135, decreased viral translation and replication in cell-based studies in a dose-dependent manner with no significant toxicity. Structural, biophysical, and biochemical characterization support an allosteric mechanism in which DMA-135 induces a conformational change in the RNA structure that stabilizes a ternary complex with the AUF1 protein that then represses translation. This mechanism was further supported by pull-down experiments in cell culture. These detailed studies establish enterovirus RNA structures as promising drug targets while revealing an approach and mechanism of action that should be broadly applicable to functional RNA targeting.

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  • ↵† Co-first authors

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Posted March 11, 2020.
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Small Molecule Targeting IRES Domain Inhibits Enterovirus 71 Replication via an Allosteric Mechanism that Stabilizes a Ternary Complex
Jesse Davila-Calderon, Neeraj Patwardhan, Liang-Yuan Chiu, Andrew Sugarman, Zhengguo Cai, Srinivasa R. Penutmutchu, Mei-Ling Li, Gary Brewer, Amanda E. Hargrove, Blanton S. Tolbert
bioRxiv 2020.03.10.981167; doi: https://doi.org/10.1101/2020.03.10.981167
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Small Molecule Targeting IRES Domain Inhibits Enterovirus 71 Replication via an Allosteric Mechanism that Stabilizes a Ternary Complex
Jesse Davila-Calderon, Neeraj Patwardhan, Liang-Yuan Chiu, Andrew Sugarman, Zhengguo Cai, Srinivasa R. Penutmutchu, Mei-Ling Li, Gary Brewer, Amanda E. Hargrove, Blanton S. Tolbert
bioRxiv 2020.03.10.981167; doi: https://doi.org/10.1101/2020.03.10.981167

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