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

作者：Lenartowicz Elzbieta; Nogales Aitor; Kierzek Elzbieta; Kierzek Ryszard; Martinez Sobrido Luis; Turner Douglas H

来源：Nucleic Acid Therapeutics, 2016, 26(5): 277-285.

DOI：10.1089/nat.2016.0619

• influenza RNA
• antisense oligonucleotides
• genomIc RNA

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.

• 出版日期2016-10