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

Jesse Davila-Calderon, Neeraj N. Patwardhan, Liang-Yuan Chiu, Andrew Sugarman, Zhengguo Cai, Srinivasa R. Penutmutchu, Mei-Ling Li, Gary Brewer (), Amanda E. Hargrove () and Blanton S. Tolbert ()
Additional contact information
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

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-18594-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18594-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-18594-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().