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Antisense Oligonucleotides Targeting Influenza A Segment 8 Genomic RNA Inhibit Viral Replication

Influenza A virus (IAV) affects 5%–10% of the world's population every year. Through genome changes, many IAV strains develop resistance to currently available anti-influenza therapeutics. Therefore, there is an urgent need to find new targets for therapeutics against this important human respi...

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Autores principales: Lenartowicz, Elzbieta, Nogales, Aitor, Kierzek, Elzbieta, Kierzek, Ryszard, Martínez-Sobrido, Luis, Turner, Douglas H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Mary Ann Liebert, Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067832/
https://www.ncbi.nlm.nih.gov/pubmed/27463680
http://dx.doi.org/10.1089/nat.2016.0619
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author Lenartowicz, Elzbieta
Nogales, Aitor
Kierzek, Elzbieta
Kierzek, Ryszard
Martínez-Sobrido, Luis
Turner, Douglas H.
author_facet Lenartowicz, Elzbieta
Nogales, Aitor
Kierzek, Elzbieta
Kierzek, Ryszard
Martínez-Sobrido, Luis
Turner, Douglas H.
author_sort Lenartowicz, Elzbieta
collection PubMed
description Influenza A virus (IAV) affects 5%–10% of the world's population every year. Through genome changes, many IAV strains develop resistance to currently available anti-influenza therapeutics. Therefore, there is an urgent need to find new targets for therapeutics against this important human respiratory pathogen. In this study, 2′-O-methyl and locked nucleic acid antisense oligonucleotides (ASOs) were designed to target internal regions of influenza A/California/04/2009 (H1N1) genomic viral RNA segment 8 (vRNA8) based on a base-pairing model of vRNA8. Ten of 14 tested ASOs showed inhibition of viral replication in Madin-Darby canine kidney cells. The best five ASOs were 11–15 nucleotides long and showed inhibition ranging from 5- to 25-fold. In a cell viability assay they showed no cytotoxicity. The same five ASOs also showed no inhibition of influenza B/Brisbane/60/2008 (Victoria lineage), indicating that they are sequence specific for IAV. Moreover, combinations of ASOs slightly improved anti-influenza activity. These studies establish the accessibility of IAV vRNA for ASOs in regions other than the panhandle formed between the 5′ and 3′ ends. Thus, these regions can provide targets for the development of novel IAV antiviral approaches.
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spelling pubmed-50678322016-10-26 Antisense Oligonucleotides Targeting Influenza A Segment 8 Genomic RNA Inhibit Viral Replication Lenartowicz, Elzbieta Nogales, Aitor Kierzek, Elzbieta Kierzek, Ryszard Martínez-Sobrido, Luis Turner, Douglas H. Nucleic Acid Ther Original Articles Influenza A virus (IAV) affects 5%–10% of the world's population every year. Through genome changes, many IAV strains develop resistance to currently available anti-influenza therapeutics. Therefore, there is an urgent need to find new targets for therapeutics against this important human respiratory pathogen. In this study, 2′-O-methyl and locked nucleic acid antisense oligonucleotides (ASOs) were designed to target internal regions of influenza A/California/04/2009 (H1N1) genomic viral RNA segment 8 (vRNA8) based on a base-pairing model of vRNA8. Ten of 14 tested ASOs showed inhibition of viral replication in Madin-Darby canine kidney cells. The best five ASOs were 11–15 nucleotides long and showed inhibition ranging from 5- to 25-fold. In a cell viability assay they showed no cytotoxicity. The same five ASOs also showed no inhibition of influenza B/Brisbane/60/2008 (Victoria lineage), indicating that they are sequence specific for IAV. Moreover, combinations of ASOs slightly improved anti-influenza activity. These studies establish the accessibility of IAV vRNA for ASOs in regions other than the panhandle formed between the 5′ and 3′ ends. Thus, these regions can provide targets for the development of novel IAV antiviral approaches. Mary Ann Liebert, Inc. 2016-10-01 2016-10-01 /pmc/articles/PMC5067832/ /pubmed/27463680 http://dx.doi.org/10.1089/nat.2016.0619 Text en © Elzbieta Lenartowicz et al., 2016; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Original Articles
Lenartowicz, Elzbieta
Nogales, Aitor
Kierzek, Elzbieta
Kierzek, Ryszard
Martínez-Sobrido, Luis
Turner, Douglas H.
Antisense Oligonucleotides Targeting Influenza A Segment 8 Genomic RNA Inhibit Viral Replication
title Antisense Oligonucleotides Targeting Influenza A Segment 8 Genomic RNA Inhibit Viral Replication
title_full Antisense Oligonucleotides Targeting Influenza A Segment 8 Genomic RNA Inhibit Viral Replication
title_fullStr Antisense Oligonucleotides Targeting Influenza A Segment 8 Genomic RNA Inhibit Viral Replication
title_full_unstemmed Antisense Oligonucleotides Targeting Influenza A Segment 8 Genomic RNA Inhibit Viral Replication
title_short Antisense Oligonucleotides Targeting Influenza A Segment 8 Genomic RNA Inhibit Viral Replication
title_sort antisense oligonucleotides targeting influenza a segment 8 genomic rna inhibit viral replication
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067832/
https://www.ncbi.nlm.nih.gov/pubmed/27463680
http://dx.doi.org/10.1089/nat.2016.0619
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