Identification of influenza A nucleoprotein as an antiviral target

Abstract

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.

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Figure 1: Chemical structures and biological activities of nucleozin and related compounds.
Figure 2: Influenza A NP is the molecular target of nucleozin.
Figure 3: Nucleozin interacts with NP and causes NP aggregation.
Figure 4: Efficacies of nucleozin in a mice H5N1 virus infection model.

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Acknowledgements

This study was supported in part by the Carol Yu Center for Infection Seed Fund for Basic Research from the University of Hong Kong, the Research Fund for the Control of Infectious Diseases and the Area of Excellence Scheme of the University Grant Council (Grant AoE/M-12/06). The Beckman Coulter Core system is a generous gift from the Hong Kong Sanatorium Hospital Doctors' Donation Fund by Y.-C. Tsao, C.-M. Chan, G. Lo, K.-M. Lai, R.K.Y. Lo, M. Tsao, B.S.S. Tse, T.-F. Tse, S.W.C. Wu, D.Y.C. Yu, R.Y.H. Yu and Y.-K. Tsao. We are grateful to R. Webster for gifts of the pHW2000 plasmids and E. Hoffmann for luciferase reporter system. We thank V. Poon, C. Chan and Q. Zhang for mice studies and K.H. Chan for virus strains. The use of Confocal Systems Core Facility provided by the LKS Faculty of Medicine, HKU, is acknowledged.

Author information

R.Y.K. and K.-Y.Y conceived the study. R.Y.K. designed and performed experiments and analyzed data. D.Y. gave conceptual advice and technical support on chemistry. L.-S.L., W.H.W.T., J.D., M.-P.C., C.-M.C. and P.W. performed experiments. J.S., L.H., and G.C. performed molecular dockings. B.-J.Z. provided animal study data. J.-D.H. gave conceptual advice on protein trafficking. J.M. constructed database and performed HTS data normalization. H.C. and Y.G. provided reverse genetics system. K.-Y.Y. did troubleshooting and provided the grant support. R.Y.K. and K.-Y.Y. supervised the study and wrote the paper.

Correspondence to Richard Y Kao or Kwok-Yung Yuen.

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The authors declare no competing financial interests.

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Supplementary Tables 1–3 and Supplementary Figs. 1–11 (PDF 657 kb)

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Kao, R., Yang, D., Lau, L. et al. Identification of influenza A nucleoprotein as an antiviral target. Nat Biotechnol 28, 600–605 (2010) doi:10.1038/nbt.1638

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