Identification of influenza A nucleoprotein as an antiviral target

Kao, Richard Y; Yang, Dan; Lau, Lai-Shan; Tsui, Wayne H W; Hu, Lihong; Dai, Jun; Chan, Mei-Po; Chan, Che-Man; Wang, Pui; Zheng, Bo-Jian; Sun, Jian; Huang, Jian-Dong; Madar, Jason; Chen, Guanhua; Chen, Honglin; Guan, Yi; Yuen, Kwok-Yung

Influenza A remains a significant public health challenge because of the emergence of antigenically shifted or highly virulent strains(1,2,3,4,5). Antiviral resistance to available drugs such as adamantanes or neuraminidase inhibitors has appeared rapidly(6,7,8,9), 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 (EC(50)) 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. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nbt.1638) contains supplementary material, which is available to authorized users.