Imino sugars for flavivirus infections of bioterror

用于生物恐怖黄病毒感染的亚氨基糖

基本信息

批准号：
7847088
负责人：
Timothy M Block
金额：
$ 9.68万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-05 至 2010-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847088
关键词：
Animal Model Animals Antiviral Agents Antiviral Response Biochemical Biochemical Markers Biological Assay Biological Markers Cattle Cell Culture System Cell physiology Chemical Structure Chemicals Clinical Clinical Pathways Dengue Virus Development Diarrhea Disease Drug Formulations Encephalitis Encephalitis Viruses Family Flaviviridae Flavivirus Flavivirus Infections Genes Glucosidase Inhibitor Goals Growth Hamsters Host Defense Human Human Cell Line In Vitro Interferons Japanese Encephalitis Viruses Japanese encephalitis virus Kyasanur Forest disease virus Lead Licensing Life Cycle Stages Ligase Omsk hemorrhagic fever virus Oral Pathway interactions Pestivirus Phase Public Health Rattus Relative (related person)Rodent Safety Secondary to Series Structure Structure-Activity Relationship Surrogate Markers System Testing Therapeutic Tick-Borne Encephalitis Virus Tick-Borne Encephalitis Viruses Time Toxic effect Upper arm Vero Cells Viral Viral Hemorrhagic Fevers Virus Virus Diseases West Nile virus Work Yellow fever virus base design genotoxicity glucosidase in vivo indexing inhibitor/antagonist meetings member mouse model pre-clinical preclinical toxicity safety study safety testing sound sugar tissue culture

项目摘要

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.

描述（由申请人提供）：这是一项开发口服亚氨基糖的申请，用于治疗生物恐怖问题的黄病毒感染，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-脱氧去甲尻霉素 (NN-DNJ) 已被证明在黄病毒感染的动物模型中有效。尽管机制健全，但该化合物的开发受到配方和毒性问题的限制。因此，将寻求具有优异活性和毒性特征的化合物。新的作用机制（MOA）和结构活性关系（SAR）信息将用于合理设计亚氨基糖；我们称之为阿尔科韦和葡萄糖韦。首先将在减产试验中测试它们抑制牛病毒性腹泻（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。在 BVDV 测试中显示出前景的化合物将被选择用于针对 WNV 和 DV 的体外和体内测试。如果根据 DV 和 WNEV 组织培养和动物模型中设定的选择性和耐受性标准发现优于 NN-DNJ 的化合物，它们将在临床前和临床开发路径中取代 NN-DNJ。