Identification of influenza A nucleoprotein as an antiviral target

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Abstract
The spread of influenza virus strains resistant to the current generation of anti-viral drugs makes the identification of new druggable targets and lead compounds of prime importance. Kao et al. show that the influenza A nucleoprotein can be targeted by a small molecule that protects mice from lethal viral challenges. Influenza A remains a significant public health challenge because of the emergence of antigenically shifted or highly virulent strains1,2,3,4,5. Antiviral resistance to available drugs such as adamantanes or neuraminidase inhibitors has appeared rapidly6,7,8,9, creating a need for new antiviral targets and new drugs for influenza virus infections. Using forward chemical genetics, we have identified influenza A nucleoprotein (NP) as a druggable target and found a small-molecule compound, nucleozin, that triggers the aggregation of NP and inhibits its nuclear accumulation. Nucleozin impeded influenza A virus replication in vitro with a nanomolar median effective concentration (EC50) and protected mice challenged with lethal doses of avian influenza A H5N1. Our results demonstrate that viral NP is a valid target for the development of small-molecule therapies.