Imino sugars for flavivirus infections of bioterror

描述(申请人提供)：这是一项开发口服亚氨基糖的申请，用于治疗引起生物恐怖的黄病毒感染，重点是西尼罗河脑炎病毒(WNEV)和登革病毒(DV)。我们的先导化合物，亚氨糖，N，-壬基-脱氧去甲吉利霉素(NN-DNJ)已被证明在黄病毒感染的动物模型中具有疗效。虽然机理合理，但该化合物的开发受到配方和毒性问题的限制。因此，人们将寻求一种具有更高活性和毒性的化合物。一种新的作用机制(MOA)和构效关系(SAR)信息将被用来合理设计亚胺类糖，我们称之为碱性病毒和糖类病毒。这些病毒将首先在减产试验中测试抑制牛病毒性腹泻(BVDV)的能力，因为它与对亚氨基糖敏感的病毒生命周期中的其他黄病毒具有相同的步骤。在BVDV测试中表现出希望的化合物将被选择用于体外和体内测试，以对抗西尼罗河病毒和DV。在DV和WNEV的组织培养和动物模型中，如果在设定的选择性和耐受性标准基础上发现了优于NN-DNJ的化合物，它们将在临床前和临床发展道路上取代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.