Antiviral agents for Flavivirus infections of bioterror

描述(由申请人提供)：这是一项识别和开发一类新的抗病毒化合物的建议，我们将其称为“葡糖病毒”，用于治疗黄病毒科成员，如西尼罗河脑炎病毒、黄热病(分别为WNEV、YFV)和鲍瓦桑病毒(PV)，这些病毒已被确定为令人担忧的生物恐怖。候选化合物是亚氨基糖-葡萄糖模拟物(因此称为“葡糖病毒”)，它竞争性地抑制细胞内质网(EA)糖链加工酶--葡萄糖苷酶。我们已经证明，从内质网获得包膜的病毒，如黄病毒和庚型肝炎病毒家族的成员，在其生命周期中有一个共同的脆弱步骤：与大多数细胞功能相比，对内质网葡萄糖苷酶功能的极度依赖。由于具有生物恐怖潜力的黄病毒在组织培养中生长困难或危险，而黄病毒家族成员牛病毒性腹泻病毒(BVDV)在组织培养中容易定量，因此我们一直使用BVDV作为替代品。我们已经鉴定了体外选择性指数为50的口服葡糖病毒，但这些化合物中的缺陷使鉴定具有更好物理性质的化合物变得可取。因此，设计合理的葡萄糖苷酶抑制剂将首先在标准的减产试验中测试其抑制BVDV的能力。我们的合作者将在组织培养和小型啮齿动物模型中测试符合一套选择性标准的化合物对YFV、WNEV和PV的抗病毒活性。在未来的研究中(除了发现计划)，符合合成和疗效标准的先导化合物将被置于包括动物PK/毒性的开发途径中，并最终在适当的情况下进行人体试验。

DESCRIPTION (provided by applicant): This is a proposal to identify and develop a new class of antiviral compounds, we call "glucovirs", for the treatment of members of the flaviviridae family such as West Nile Encephalitis Virus, Yellow Fever (WNEV, YFV respectively) and Powassan viruses (PV) that have been identified as being of bioterror concern. The candidate compounds are imino sugar glucose mimetics (hence, "glucovirs") that competitively inhibit the cellular endoplasmic reticular (EA) glycan-processing enzyme, glucosidase. We have shown that viruses that gain their envelopes from the ER, such as members of the flavi and hepadnavirus families, share a common vulnerable step in their life cycle: extreme dependency upon ER glucosidase function as compared with most cellular functions. Since the flaviviruses of bioterror potential are difficult or dangerous to grow in tissue culture, but the flavivirus family member bovine viral diarrhea virus (BVDV) is easily quantified in tissue culture, we have been using BVDV as a surrogate. We have already identified orally available glucovirs with in vitro selectivity indexes of 50, but flaws in these compounds make it desirable to identify compounds with better physical properties. Therefore, rationally designed glucosidase inhibitors will first be tested for the ability to inhibit BVDV, in a standard yield reduction assay. Compounds meeting a set criteria of selectivity will be tested for antiviral activity against YFV, WNEV and PV by our collaborator, in a tissue culture and, if appropriate, small rodent models. In future studies (beyond the discovery program), lead compounds, meeting synthesis and efficacy standards, will then be placed in a development pathway including animal PK/toxicity and ultimately, if appropriate, human trials.