Abstract

This is an application to develop an orally available imino sugar for the treatment of flaviviruses infections of bioterror concern, with a focus upon West Nile Encephalitis virus (WNEV) and Dengue Viruses (DV). Our lead compound, the imino sugar, N, -nonyl-deoxynorjirimycin (NN-DNJ) has been shown to have efficacy in animal models of flavivirus infection. Although sound in mechanism, development of this compound was limited by formulation and toxicity issues. Therefore, a compound with a superior activity and toxicity profile will be sought. A new mechanism of action (MOA) and structure activity relationship (SAR) information will be used to rationally design imino sugars;we call alkovirs and glucovirs. These will first be tested for the ability to inhibit bovine viral diarrhea (BVDV) in yield reduction assays, since it shares the same step as other flaviviruses in the virus life cycle that is sensitive to the imino sugars. Compounds that show promise in BVDV testing will be selected for in vitro and in vivo testing against WNV and DV. If compounds are found that are superior to NN-DNJ on the basis of set criteria of selectivity and tolerability in tissue culture and animal models of DV and WNEV, they will replace NN-DNJ in the pre-clinical and clinical development path.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI061441-05
Application #
7564829
Study Section
Special Emphasis Panel (ZAI1-AR-M (M1))
Program Officer
Tseng, Christopher K
Project Start
2005-02-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$1,717,119
Indirect Cost

  Institution

Name
Drexel University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Chang, Jinhong; Warren, Travis K; Zhao, Xuesen et al. (2013) Small molecule inhibitors of ER ?-glucosidases are active against multiple hemorrhagic fever viruses. Antiviral Res 98:432-40
Guo, Fang; Mead, Jennifer; Aliya, Nishat et al. (2012) RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response. PLoS One 7:e42583
Yu, Wenquan; Gill, Tina; Wang, Lijuan et al. (2012) Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection. J Med Chem 55:6061-75
Guo, Haitao; Pan, Xiaoben; Mao, Richeng et al. (2011) Alkylated porphyrins have broad antiviral activity against hepadnaviruses, flaviviruses, filoviruses, and arenaviruses. Antimicrob Agents Chemother 55:478-86
Chang, Jinhong; Schul, Wouter; Yip, Andy et al. (2011) Competitive inhibitor of cellular ýý-glucosidases protects mice from lethal dengue virus infection. Antiviral Res 92:369-71
Qu, Xiaowang; Pan, Xiaoben; Weidner, Jessica et al. (2011) Inhibitors of endoplasmic reticulum alpha-glucosidases potently suppress hepatitis C virus virion assembly and release. Antimicrob Agents Chemother 55:1036-44
Chang, Jinhong; Schul, Wouter; Butters, Terry D et al. (2011) Combination of ýý-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. Antiviral Res 89:26-34
Weidner, Jessica M; Jiang, Dong; Pan, Xiao-Ben et al. (2010) Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms. J Virol 84:12646-57
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
Xu, Chunxiao; Guo, Haitao; Pan, Xiao-Ben et al. (2010) Interferons accelerate decay of replication-competent nucleocapsids of hepatitis B virus. J Virol 84:9332-40

Showing the most recent 10 out of 21 publications