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A general strategy to inhibiting viral −1 frameshifting based on upstream attenuation duplex formation

Viral −1 programmed ribosomal frameshifting (PRF) as a potential antiviral target has attracted interest because many human viral pathogens, including human immunodeficiency virus (HIV) and coronaviruses, rely on −1 PRF for optimal propagation. Efficient eukaryotic −1 PRF requires an optimally place...

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Autores principales: Hu, Hao-Teng, Cho, Che-Pei, Lin, Ya-Hui, Chang, Kung-Yao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705660/
https://www.ncbi.nlm.nih.gov/pubmed/26612863
http://dx.doi.org/10.1093/nar/gkv1307
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author Hu, Hao-Teng
Cho, Che-Pei
Lin, Ya-Hui
Chang, Kung-Yao
author_facet Hu, Hao-Teng
Cho, Che-Pei
Lin, Ya-Hui
Chang, Kung-Yao
author_sort Hu, Hao-Teng
collection PubMed
description Viral −1 programmed ribosomal frameshifting (PRF) as a potential antiviral target has attracted interest because many human viral pathogens, including human immunodeficiency virus (HIV) and coronaviruses, rely on −1 PRF for optimal propagation. Efficient eukaryotic −1 PRF requires an optimally placed stimulator structure downstream of the frameshifting site and different strategies targeting viral −1 PRF stimulators have been developed. However, accessing particular −1 PRF stimulator information represents a bottle-neck in combating the emerging epidemic viral pathogens such as Middle East respiratory syndrome coronavirus (MERS-CoV). Recently, an RNA hairpin upstream of frameshifting site was shown to act as a cis-element to attenuate −1 PRF with mechanism unknown. Here, we show that an upstream duplex formed in-trans, by annealing an antisense to its complementary mRNA sequence upstream of frameshifting site, can replace an upstream hairpin to attenuate −1 PRF efficiently. This finding indicates that the formation of a proximal upstream duplex is the main determining factor responsible for −1 PRF attenuation and provides mechanistic insight. Additionally, the antisense-mediated upstream duplex approach downregulates −1 PRF stimulated by distinct −1 PRF stimulators, including those of MERS-CoV, suggesting its general application potential as a robust means to evaluating viral −1 PRF inhibition as soon as the sequence information of an emerging human coronavirus is available.
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spelling pubmed-47056602016-01-11 A general strategy to inhibiting viral −1 frameshifting based on upstream attenuation duplex formation Hu, Hao-Teng Cho, Che-Pei Lin, Ya-Hui Chang, Kung-Yao Nucleic Acids Res Molecular Biology Viral −1 programmed ribosomal frameshifting (PRF) as a potential antiviral target has attracted interest because many human viral pathogens, including human immunodeficiency virus (HIV) and coronaviruses, rely on −1 PRF for optimal propagation. Efficient eukaryotic −1 PRF requires an optimally placed stimulator structure downstream of the frameshifting site and different strategies targeting viral −1 PRF stimulators have been developed. However, accessing particular −1 PRF stimulator information represents a bottle-neck in combating the emerging epidemic viral pathogens such as Middle East respiratory syndrome coronavirus (MERS-CoV). Recently, an RNA hairpin upstream of frameshifting site was shown to act as a cis-element to attenuate −1 PRF with mechanism unknown. Here, we show that an upstream duplex formed in-trans, by annealing an antisense to its complementary mRNA sequence upstream of frameshifting site, can replace an upstream hairpin to attenuate −1 PRF efficiently. This finding indicates that the formation of a proximal upstream duplex is the main determining factor responsible for −1 PRF attenuation and provides mechanistic insight. Additionally, the antisense-mediated upstream duplex approach downregulates −1 PRF stimulated by distinct −1 PRF stimulators, including those of MERS-CoV, suggesting its general application potential as a robust means to evaluating viral −1 PRF inhibition as soon as the sequence information of an emerging human coronavirus is available. Oxford University Press 2016-01-08 2015-11-26 /pmc/articles/PMC4705660/ /pubmed/26612863 http://dx.doi.org/10.1093/nar/gkv1307 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Molecular Biology
Hu, Hao-Teng
Cho, Che-Pei
Lin, Ya-Hui
Chang, Kung-Yao
A general strategy to inhibiting viral −1 frameshifting based on upstream attenuation duplex formation
title A general strategy to inhibiting viral −1 frameshifting based on upstream attenuation duplex formation
title_full A general strategy to inhibiting viral −1 frameshifting based on upstream attenuation duplex formation
title_fullStr A general strategy to inhibiting viral −1 frameshifting based on upstream attenuation duplex formation
title_full_unstemmed A general strategy to inhibiting viral −1 frameshifting based on upstream attenuation duplex formation
title_short A general strategy to inhibiting viral −1 frameshifting based on upstream attenuation duplex formation
title_sort general strategy to inhibiting viral −1 frameshifting based on upstream attenuation duplex formation
topic Molecular Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705660/
https://www.ncbi.nlm.nih.gov/pubmed/26612863
http://dx.doi.org/10.1093/nar/gkv1307
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