The present disclosure provides methods and compositions relating to a polynucleotide comprising a dsRNA region that is complementary to a particular region of the NS1 gene segment in the influenza virus genome that targets a sequence comprising two overlapping reading frames, one encoding NS1 and the second encoding the NEP polypeptide. Thus, the polynucleotide of the invention is able to target two message RNAs and is effective at inhibiting the replication of influenza virus in a cell.
