Imino sugars for flavivirus infections of bioterror

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DESCRIPTION (provided by applicant): 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.