Screening for antivirals against flaviviruses

描述(申请人提供)：病毒性出血热(VHF)是指由四个病毒家族的成员引起的一组疾病。这些病毒可导致危及生命的疾病，其症状为皮下、内脏或从各种体孔出血。严重的病例还可能表现为休克、神经系统功能障碍、昏迷、精神错乱、癫痫发作和肾功能衰竭。一些甚高频特工因滥用生物武器/生物恐怖主义而受到怀疑。黄病毒科的成员是导致VHF的病毒病原体之一。该家族中的病毒都是包膜正义RNA病毒，在基因组结构和复制周期上具有许多相似的特征。尽管利巴韦林在治疗某些VHF病例中有效，并显示出对包括YFV在内的一些RNA病毒的一些活性，但对导致VHF的任何药物都没有特定的治疗方法。这种应用是对开发这些疾病的特定治疗方式的挑战的回应。我们计划开发基于细胞的检测方法，用于测试和筛选对某些黄病毒具有抗病毒活性的化合物。这些分析将基于含有结构性复制亚基因组复制子的细胞系，并以为丙型肝炎病毒开发的原型系统为模型。我们的方法适用于一些引起病毒性出血热的病毒，如A类生物恐怖分子(壁虱传播的脑炎病毒、凯萨努尔森林病病毒、鄂木斯克出血热病毒等)和C类制剂(黄热病病毒、登革热病毒等)。

DESCRIPTION (provided by applicant): Viral hemorrhagic fever (VHF) refers to a group of illnesses that are caused by members of four families of viruses. These viruses can cause life-threatening disease with signs of bleeding under the skin, in internal organs, or from various body orifices. Severe cases may also show shock, nervous system malfunction, coma, delirium, seizures and renal failure. Some VHF agents have been suspect for abuse in biowarfare/bioterrorism. Members of the family Flaviviridae are among the viral agents that cause VHF. Viruses in this family are all enveloped positive-sense RNA viruses with many similar features in their genome structure and replication cycle. There is no specific treatment for any of the agents that cause VHF, although ribavirin has been effective in treating some cases of VHF and shows some activity against a number of RNA viruses including YFV.This application is in response to the challenge to develop specific treatment modalities for these diseases. We plan to develop cell-based assays for testing and screening of compounds with antiviral activity against certain flaviviruses. These assays will be based on cell lines that harbor a constitutively replicating subgenomic replicon and are modeled on a prototype system developed for hepatitis C virus. Our approach is applicable to a number of viruses that cause viral hemorrhagic fever such as category A bioterrorism agents (tick-borne encephalitis virus, Kyasanur Forest disease virus, Omsk hemorrhagic fever virus, etc.) and category C agents (yellow fever virus, Dengue virus, etc.).