Identification of Influenza A Nucleoprotein As an Antiviral Target

Overview

Journal Nat Biotechnol

Specialty Biotechnology

Date 2010 Jun 1

PMID 20512121

Citations 123

Authors

Richard Y Kao

Dan Yang

Lai-Shan Lau

Wayne H W Tsui

Lihong Hu

Jun Dai

Mei-Po Chan

Che-Man Chan

Pui Wang

Bo-Jian Zheng

Jian Sun

Jian-Dong Huang

Jason Madar

Guanhua Chen

Honglin Chen

Yi Guan

Kwok-Yung Yuen

Affiliations

Soon will be listed here.

Abstract

Influenza A remains a significant public health challenge because of the emergence of antigenically shifted or highly virulent strains. Antiviral resistance to available drugs such as adamantanes or neuraminidase inhibitors has appeared rapidly, 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.

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References

Hoffmann E, Neumann G, Kawaoka Y, HOBOM G, Webster R . A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci U S A. 2000; 97(11):6108-13. PMC: 18566. DOI: 10.1073/pnas.100133697. View

Campanacci V, Lartigue A, Hallberg B, Jones T, Giudici-Orticoni M, Tegoni M . Moth chemosensory protein exhibits drastic conformational changes and cooperativity on ligand binding. Proc Natl Acad Sci U S A. 2003; 100(9):5069-74. PMC: 154299. DOI: 10.1073/pnas.0836654100. View

Wu W, Sun Y, Pante N . Nuclear import of influenza A viral ribonucleoprotein complexes is mediated by two nuclear localization sequences on viral nucleoprotein. Virol J. 2007; 4:49. PMC: 1891284. DOI: 10.1186/1743-422X-4-49. View

Ye Q, Krug R, Tao Y . The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA. Nature. 2006; 444(7122):1078-82. DOI: 10.1038/nature05379. View

Portela A, Digard P . The influenza virus nucleoprotein: a multifunctional RNA-binding protein pivotal to virus replication. J Gen Virol. 2002; 83(Pt 4):723-734. DOI: 10.1099/0022-1317-83-4-723. View

Gubareva L, Bethell R, Hart G, Murti K, Penn C, Webster R . Characterization of mutants of influenza A virus selected with the neuraminidase inhibitor 4-guanidino-Neu5Ac2en. J Virol. 1996; 70(3):1818-27. PMC: 190009. DOI: 10.1128/JVI.70.3.1818-1827.1996. View

Davey J, Dimmock N, Colman A . Identification of the sequence responsible for the nuclear accumulation of the influenza virus nucleoprotein in Xenopus oocytes. Cell. 1985; 40(3):667-75. DOI: 10.1016/0092-8674(85)90215-6. View

Dharan N, Gubareva L, Meyer J, Okomo-Adhiambo M, McClinton R, Marshall S . Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA. 2009; 301(10):1034-41. DOI: 10.1001/jama.2009.294. View

Kao R, To A, Ng L, Tsui W, Lee T, Tsoi H . Characterization of SARS-CoV main protease and identification of biologically active small molecule inhibitors using a continuous fluorescence-based assay. FEBS Lett. 2004; 576(3):325-30. PMC: 7134596. DOI: 10.1016/j.febslet.2004.09.026. View

10.

Wong S, Yuen K . Avian influenza virus infections in humans. Chest. 2006; 129(1):156-68. PMC: 7094746. DOI: 10.1378/chest.129.1.156. View

11.

Lackenby A, Thompson C, Democratis J . The potential impact of neuraminidase inhibitor resistant influenza. Curr Opin Infect Dis. 2008; 21(6):626-38. DOI: 10.1097/QCO.0b013e3283199797. View

12.

Zheng B, Chan K, Lin Y, Zhao G, Chan C, Zhang H . Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc Natl Acad Sci U S A. 2008; 105(23):8091-6. PMC: 2430364. DOI: 10.1073/pnas.0711942105. View

13.

Moscona A . Global transmission of oseltamivir-resistant influenza. N Engl J Med. 2009; 360(10):953-6. DOI: 10.1056/NEJMp0900648. View

14.

Niepmann M, Zheng J . Discontinuous native protein gel electrophoresis. Electrophoresis. 2006; 27(20):3949-51. DOI: 10.1002/elps.200600172. View

15.

Yuen K, Chan P, Peiris M, Tsang D, Que T, Shortridge K . Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet. 1998; 351(9101):467-71. DOI: 10.1016/s0140-6736(98)01182-9. View

16.

Kao R, Tsui W, Lee T, Tanner J, Watt R, Huang J . Identification of novel small-molecule inhibitors of severe acute respiratory syndrome-associated coronavirus by chemical genetics. Chem Biol. 2004; 11(9):1293-9. PMC: 7128553. DOI: 10.1016/j.chembiol.2004.07.013. View

17.

Regoes R, Bonhoeffer S . Emergence of drug-resistant influenza virus: population dynamical considerations. Science. 2006; 312(5772):389-91. DOI: 10.1126/science.1122947. View

18.

Stockwell B . Chemical genetics: ligand-based discovery of gene function. Nat Rev Genet. 2001; 1(2):116-25. PMC: 3171795. DOI: 10.1038/35038557. View

19.

Min J, Krug R . The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2'-5' oligo (A) synthetase/RNase L pathway. Proc Natl Acad Sci U S A. 2006; 103(18):7100-5. PMC: 1459024. DOI: 10.1073/pnas.0602184103. View

20.

Strausberg R, Schreiber S . From knowing to controlling: a path from genomics to drugs using small molecule probes. Science. 2003; 300(5617):294-5. DOI: 10.1126/science.1083395. View