Imino sugars for flavivirus infections of bioterror

描述（由申请人提供）：这是一份开发口服亚氨基糖的申请，用于治疗生物恐怖关注的黄病毒感染，重点是西尼罗脑炎病毒（WNEV）和登革热病毒（DV）。我们的先导化合物亚氨基糖N， -壬基脱氧去甲霉素（NN-DNJ）已被证明对黄病毒感染的动物模型有效。虽然机理良好，但该化合物的发展受到配方和毒性问题的限制。因此，需要寻找一种具有较强活性和毒性的化合物。新的作用机制（MOA）和构效关系（SAR）信息将用于合理设计亚糖；我们称之为碱病毒和糖病毒。它们将首先在产量降低试验中测试抑制牛病毒性腹泻（BVDV）的能力，因为它与病毒生命周期中对亚氨基糖敏感的其他黄病毒具有相同的步骤。将选择在BVDV测试中有希望的化合物进行针对西尼罗河病毒和DV的体内和体外测试。如果在DV和WNEV的组织培养和动物模型中，根据设定的选择性和耐受性标准，发现化合物优于NN-DNJ，它们将在临床前和临床开发道路上取代NN-DNJ。

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.