Structural architecture of the human long non-coding RNA-PAAN as a potential target for anti-influenza drug development

Influenza A virus (IAV) is considered one of the most dangerous pathogens in the world because of its great variability. Available anti-influenza drugs suffer from the rapid emergence of drug resistance. Thus, there is an urgent need to develop new antiviral strategies with new mechanisms of action and reduced drug resistance potential. Host lncRNAs are much less variable than influenza RNA/protein; therefore, they can be a new and universal aim of antiviral therapy. Recently, studies have revealed the interferon-independent host lncRNAs-PAAN that interacts with the influenza virus PA protein to promote viral replication. Until now, data concerning the lncRNA-PAAN structure in vitro and in biological environments have not been discovered. Here, for the first time, we used chemical mapping and the SHAPE method to propose the secondary structure of lncRNA-PAAN in vitro and in the cellular environment. We discuss the experimental and computational approaches that have led to distinct structural models. Finally, we defined the structural motifs of lncRNA-PAAN of potential functionality forming during influenza A infection and designed lncRNA-PAAN structure-specific antisense oligonucleotides (ASOs). Several of these ASOs significantly lowered the level of lncRNA-PAAN and inhibited IAV infection. Our findings not only advance our understanding of the complexity of the IAV-host interactions but also could be used for designing a new anti-influenza A strategy targeting the host lncRNAs.