West Nile (WN) and dengue (DEN) viruses are emerging flaviviruses and potential biodefense pathogens that cause significant human diseases. Neither vaccine nor effective chemotherapy is currently available for WN and DEN infections in humans. The objective of this project is to identify novel inhibitors of WN and DEN viruses. We will accomplish the following two interim objectives. (1) Develop novel high-throughput assays to screen for inhibitors of WN and DEN replication. Using subgenomic WN and DEN replicons expressing reporter genes, we will develop reporting cell lines that can be used for high-throughput screening of inhibitors against all targets involved in viral replication. As a proof-of-principle, we have already established such a reporting cell line for high-throughput screening of WN inhibitors. We will develop a similar high-throughput assay for anti-DEN drug discovery. (2) Identify new classes of inhibitors of WN and DEN and analyze their modes of action. In collaboration with ViroPharma, Inc., we will use the high-throughput assays to identify new classes of WN and DEN inhibitors through screening a large number of compound libraries. We will study the potential inhibitors by (i) examining whether the compounds can inhibit other members of the flaviviruses, and (ii) analyzing the modes of action of the compounds through both biochemical (enzyme assays) and genetic approaches (selection of compound-resistant viruses). The high-throughput assay-approach proposed in this application has been proven to be fruitful in antiviral drug discovery (e.g. hepatitis C virus). At the completion of these studies, we expect to have identified novel inhibitors of WN and DEN, and to have determined the modes of action of these inhibitors. These results will be significant, because they will form a foundation for development of an efficacious chemotherapy of WN and DEN infections. The reporting cell lines developed in this project will also be useful for many aspects of flavivirus research such as studying genome packaging and viral particle formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI061193-03
Application #
7072200
Study Section
Special Emphasis Panel (ZAI1-AR-M (M1))
Program Officer
Tseng, Christopher K
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$374,593
Indirect Cost
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204
Lim, Pei-Yin; Keating, Julie A; Hoover, Spencer et al. (2011) A thiopurine drug inhibits West Nile virus production in cell culture, but not in mice. PLoS One 6:e26697
Dong, Hongping; Liu, Lihui; Zou, Gang et al. (2010) Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase. J Biol Chem 285:32586-95
Jiang, Dong; Weidner, Jessica M; Qing, Min et al. (2010) Identification of five interferon-induced cellular proteins that inhibit west nile virus and dengue virus infections. J Virol 84:8332-41
Zhang, Bo; Dong, Hongping; Ye, Hanqing et al. (2010) Genetic analysis of West Nile virus containing a complete 3'CSI RNA deletion. Virology 408:138-45
Zou, Gang; Puig-Basagoiti, Francesc; Zhang, Bo et al. (2009) A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor. Virology 384:242-52
Ma, Dongling; Jiang, Dong; Qing, Min et al. (2009) Antiviral effect of interferon lambda against West Nile virus. Antiviral Res 83:53-60
Puig-Basagoiti, Francesc; Qing, Min; Dong, Hongping et al. (2009) Identification and characterization of inhibitors of West Nile virus. Antiviral Res 83:71-9
Zou, Gang; Zhang, Bo; Lim, Pei-Yin et al. (2009) Exclusion of West Nile virus superinfection through RNA replication. J Virol 83:11765-76
Qing, Min; Yang, Feng; Zhang, Bo et al. (2009) Cyclosporine inhibits flavivirus replication through blocking the interaction between host cyclophilins and viral NS5 protein. Antimicrob Agents Chemother 53:3226-35
Dong, Hongping; Zhang, Bo; Shi, Pei-Yong (2008) Flavivirus methyltransferase: a novel antiviral target. Antiviral Res 80:1-10

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