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

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...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications Vol. 11; no. 1; pp. 1 - 13
Main Authors: Davila-Calderon, Jesse, Patwardhan, Neeraj N., Chiu, Liang-Yuan, Sugarman, Andrew, Cai, Zhengguo, Penutmutchu, Srinivasa R., Li, Mei-Ling, Brewer, Gary, Hargrove, Amanda E., Tolbert, Blanton S.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 22-09-2020
Nature Portfolio
Subjects:
101/6
13
13/1
49
631/154/555
631/45/500
Humanities and Social Sciences
multidisciplinary
Science
Science (multidisciplinary)
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Human enterovirus 71 (EV71) contains an internal ribosome entry site (IRES) that promotes translation of viral RNA. Here the authors show that an antiviral small molecule DMA-135 binds to the EV71 IRES RNA, inducing conformational change and stabilizing a ternary complex to repress translation.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-18594-3