2. Academic Validation
  3. IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex

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

  • Nat Commun. 2020 Sep 22;11(1):4775. doi: 10.1038/s41467-020-18594-3.
Jesse Davila-Calderon  # 1,  Neeraj N Patwardhan  # 2,  Liang-Yuan Chiu 1,  Andrew Sugarman 1,  Zhengguo Cai 2,  Srinivasa R Penutmutchu 1,  Mei-Ling Li 3,  Gary Brewer 4,  Amanda E Hargrove 5,  Blanton S Tolbert 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA.
  • 2 Department of Chemistry, Duke University, Durham, NC, USA.
  • 3 Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA.
  • 4 Department of Biochemistry and Molecular Biology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA. [email protected].
  • 5 Department of Chemistry, Duke University, Durham, NC, USA. [email protected].
  • 6 Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA. [email protected].
  • # Contributed equally.
PMID: 32963221 DOI: 10.1038/s41467-020-18594-3
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.

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