Small Molecule Inhibitors of Smallpox Virus Replication

描述(由调查人员提供)：天花病毒(天花)是一种潜在的生物武器制剂，因为它易于传播，可在人与人之间传播，并有可能导致广泛的疾病和死亡。天花病毒被疾病控制和预防中心(CDC)列为A类生物武器制剂。目前，还没有FDA批准的抗病毒药物来预防或治疗天花感染。我们天花病毒生物防御计划的总体目标是发现和开发用于预防和治疗天花病毒感染的小分子药物。这一阶段应用的具体目的是：1.建立一种有效的病毒特异性高通量筛选方法，使用牛痘病毒(BSL-2)替代真正的天花病毒。2.从ViroPharma拥有40多万种小分子化合物的专利化学多样性文库中确定针对牛痘病毒野生型和抗药性变种的特定抑制剂。3.对抑制剂化合物(“HITS”)的化学可操作性、抗病毒效力以及光谱和选择性进行表征，以确定有希望的“高质量HITS”。4.在细胞培养中(通过合作实验室进行)确认质量靶标对真实天花病毒的抗病毒特异性和选择性；5.研究“已确认质量靶标”的抗病毒作用机制；6.对已确认的质量靶标进行药物代谢、遗传毒性和药代动力学初步评价。第一阶段工作的最终结果将是确定针对天花病毒的特定质量命中。这些化合物在第二阶段的进展将包括：(1)Hit-to-Lead药物化学，以确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)针对抗病毒效力、抗病毒活性的选择性和光谱以及药物代谢和药代动力学特性的先导化合物优化；(3)作用机制和耐药性表征；以及(4)在合适的动物模型中的疗效评估。在第二阶段结束时，我们预计已经确定了至少一种临床前候选化合物，适合进入预防和治疗天花病毒感染的正式IND毒理学和模型动物疗效评估。

DESCRIPTION (provided by investigator): Smallpox virus (variola) is a potential biological weapons agent due to its ease of dissemination, person to- person transmissibility and potential to cause widespread illness and death. Smallpox virus is classified as a Category A bioweapons agent by the Centers for Disease Control and Prevention (CDC). Currently, there are no FDA-approved antiviral drugs to prevent or treat smallpox infection. The overall goal of our Smallpox Virus Biodefense Program is to discover and develop small molecule drugs for prevention and treatment of smallpox virus infection. The specific aims of this Phase 1 application are to: 1. Establish a validated virus-specific high throughput-screening assay using a cowpox virus (BSL-2) surrogate for authentic variola virus. 2. Identify specific inhibitors that target wild type and drug resistant variants of cowpox virus from VIROPHARMA's proprietary chemically diverse library of over 400,000 small molecule compounds. 3. Characterize inhibitor compounds ("hits") for chemical tractability, antiviral potency and spectrum and selectivity in order to identify promising "quality hits". 4. Confirm antiviral specificity and selectivity of quality hits against the authentic variola virus in cell culture (performed through collaborating laboratories); 5. Investigate the mechanism of antiviral action of "confirmed quality hits"; and 6. Conduct initial drug metabolism, genotoxicity & pharmacokinetic evaluations on confirmed quality hits. The end result of Phase 1 work will be identification of quality hits specific for variola virus. 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) efficacy evaluations in suitable animal models. At the end of Phase 2, we anticipate to have identified at least one pre-clinical candidate compound that is suitable for advancement into formal IND toxicological and model animal efficacy evaluations for the prevention and treatment of smallpox virus infection.