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IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex

Author

Listed:
  • Jesse Davila-Calderon

    (Case Western Reserve University)

  • Neeraj N. Patwardhan

    (Duke University)

  • Liang-Yuan Chiu

    (Case Western Reserve University)

  • Andrew Sugarman

    (Case Western Reserve University)

  • Zhengguo Cai

    (Duke University)

  • Srinivasa R. Penutmutchu

    (Case Western Reserve University)

  • Mei-Ling Li

    (Rutgers Robert Wood Johnson Medical School)

  • Gary Brewer

    (Rutgers Robert Wood Johnson Medical School)

  • Amanda E. Hargrove

    (Duke University)

  • Blanton S. Tolbert

    (Case Western Reserve University)

Abstract

Enterovirus 71 (EV71) poses serious threats to human health, particularly in Southeast Asia, and no drugs or vaccines are available. Previous work identified the stem loop II structure of the EV71 internal ribosomal entry site as vital to viral translation and a potential target. After screening an RNA-biased library using a peptide-displacement assay, we identify DMA-135 as a dose-dependent inhibitor of viral translation and replication with no significant toxicity in cell-based studies. 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, thus repressing translation. This mechanism is 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.

Suggested Citation

  • Jesse Davila-Calderon & Neeraj N. Patwardhan & Liang-Yuan Chiu & Andrew Sugarman & Zhengguo Cai & Srinivasa R. Penutmutchu & Mei-Ling Li & Gary Brewer & Amanda E. Hargrove & Blanton S. Tolbert, 2020. "IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18594-3
    DOI: 10.1038/s41467-020-18594-3
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