IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex
Year: 2020
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,380
Awards: Harnessing Small Molecules to Probe the Structure and Function of Regulatory RNAs, Graduate Training in Cell and Molecular Biology, G5520316217, G5950577451, The Center for HIV RNA Studies (CRNA), G9000350844, Defining the Structural Mechanisms of RNP Complexes that Regulate Enterovirus Translation
OpenAlex ID: W3081871273