Small Molecule Inhibitors of Smallpox Virus Replication

描述（由研究者提供）：天花病毒（天花）是一种潜在的生物武器制剂，因为其易于传播、人与人之间的传播性和导致广泛疾病和死亡的可能性。天花病毒被疾病控制和预防中心（CDC）列为A类生物武器。目前，没有FDA批准的抗病毒药物来预防或治疗天花感染。我们的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。第一阶段申请的具体目标是：1。使用真实天花病毒的牛痘病毒（BSL-2）替代品建立经验证的病毒特异性高通量筛选试验。2.从VIROPHARMA专有的化学多样性超过400，000种小分子化合物库中识别针对牛痘病毒野生型和耐药变体的特异性抑制剂。3.表征抑制剂化合物（“命中”）的化学易处理性、抗病毒效力以及光谱和选择性，以确定有希望的“质量命中”。4.确认细胞培养物中针对真实天花病毒的质量命中的抗病毒特异性和选择性（通过合作实验室进行）; 5.研究“确认质量命中”的抗病毒作用机制;以及6.对已确认的药物质量进行初始药物代谢、遗传毒性和药代动力学评价。第1阶段工作的最终结果将是鉴定天花病毒特异性的质量命中。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功效评价。在第2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，适用于进入正式的IND毒理学和模型动物有效性评价，用于预防和治疗天花病毒感染。

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.