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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508794/ https://www.ncbi.nlm.nih.gov/pubmed/32963221 http://dx.doi.org/10.1038/s41467-020-18594-3 |
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author | 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. |
author_facet | 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. |
author_sort | Davila-Calderon, Jesse |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7508794 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75087942020-10-08 IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex 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. Nat Commun Article 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. Nature Publishing Group UK 2020-09-22 /pmc/articles/PMC7508794/ /pubmed/32963221 http://dx.doi.org/10.1038/s41467-020-18594-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article 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. IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex |
title | IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex |
title_full | IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex |
title_fullStr | IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex |
title_full_unstemmed | IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex |
title_short | IRES-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex |
title_sort | ires-targeting small molecule inhibits enterovirus 71 replication via allosteric stabilization of a ternary complex |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508794/ https://www.ncbi.nlm.nih.gov/pubmed/32963221 http://dx.doi.org/10.1038/s41467-020-18594-3 |
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