Antiviral Drugs Against Hemorrhagic Fever Viruses

描述（由研究者提供）：病毒性出血热（VHF）是一种以发热、多器官受累和广泛血管损伤为特征的严重疾病。出血热病毒（HFV），特别是拉沙热（沙粒病毒科）、裂谷热（布尼亚病毒科）以及埃博拉和马尔堡（丝状病毒科）病毒是潜在的生物武器剂，因为它们易于传播、人与人之间的传染性和造成广泛疾病和死亡的可能性。这些HFV被疾病控制和预防中心（CDC）列为A类生物武器。目前，还没有获得许可的疫苗或FDA批准的抗病毒药物来预防或治疗VHF。我们的A类病毒生物防御计划的总体目标是发现和开发针对HFV的小分子药物。第一阶段申请的具体目标是： 1.建立几种经验证的病毒特异性高通量筛选试验，涉及密切相关的替代物、BSL-2病毒或沙粒病毒、布尼亚病毒和丝状病毒的试验系统; 2.使用这些病毒特异性检测试剂盒，从VIROPHARMA专有的、化学成分多样的超过400，000种小分子化合物库中鉴定针对靶病毒的特异性抑制剂; 3.表征抑制剂化合物（命中）的化学易处理性，抗病毒效力和选择性，以及抗病毒活性谱，以确定有希望的“质量命中”; 4.确认针对细胞培养物中真实靶向A类病毒的抗病毒特异性和质量命中选择性（通过合作实验室进行）;以及 5.启动药物代谢，遗传毒性和药代动力学评估确认质量命中。 第1阶段工作的最终结果将是鉴定至少两种靶向病毒因子的特异性质量命中。这些化合物在II期的进展将包括：（1）命中先导药物化学，以鉴定具有良好化学结构-生物活性关系（SAR）潜力的先导化合物;（2）先导化合物的抗病毒效力、抗病毒活性的选择性和谱以及药物代谢和药代动力学性质的优化;（3）作用机制和耐药性表征;和（4）在合适的动物模型中的安全性和有效性评价。

DESCRIPTION (provided by investigator): Viral hemorrhagic fevers (VHFs) are severe illnesses characterized by fever, multiple organ involvement and extensive vascular damage. Hemorrhagic fever viruses (HFVs), in particular Lassa fever (Arenaviridae), Rift Valley fever (Bunyaviridae), and Ebola and Marburg (Filoviridae) viruses are potential biological weapons agents due to their ease of dissemination, person-to-person transmissibility and potential to cause widespread illness and death. These HFVs are classified as Category A bioweapons agents by the Centers for Disease Control and Prevention (CDC). Currently, there are no licensed vaccines or FDA-approved antiviral drugs to prevent or treat VHF. The overall goal of our Category A Virus Biodefense Program is to discover and develop small molecule drugs for HFVs. The specific aims of this Phase 1 application are to: 1. Establish several validated virus-specific high throughput screening assays involving closely related surrogate, BSL-2 viruses or assay systems for arenaviruses, bunyaviruses and filoviruses; 2. Identify inhibitors specific for the targeted viruses from the VIROPHARMA proprietary, chemically diverse library of over 400,000 small molecule compounds using these virus-specific assays; 3. Characterize inhibitor compounds (hits) for chemical tractability, antiviral potency and selectivity, and spectrum of antiviral activity in order to identify promising "quality hits"; 4. Confirm antiviral specificity and selectivity of quality hits against the authentic targeted Category A viruses in cell culture (performed through collaborating laboratories); and 5. Initiate drug metabolism, genotoxicity & pharmacokinetic evaluations on confirmed quality hits. The end result of Phase 1 work will be identification of quality hits specific for at least two targeted viral agents. Advancement of these compounds in Phase 2 will involve: (1) hit-to-lead medicinal chemistry to identify leads with good potential for chemical structure-biological activity relationships (SAR); (2) lead compound optimization for antiviral potency, selectivity and spectrum of antiviral activity and drug metabolic and pharmacokinetics properties; (3) mechanism of action and drug resistance characterizations; and (4) safety and efficacy evaluations in suitable animal models.