Inhibiting poxvirus phosphatases: therapy and biodefense

描述（由申请人提供）：天花病毒的释放重新出现，天花病毒在20世纪70年代末被宣布为对人类的自然威胁，是最令人恐惧的生物恐怖主义场景之一。因此，强烈需要开发有效的抗病毒治疗剂，其将容易地施用于暴露个体并且将减少或消除疾病的发展和传播。由于天花（VAR）和牛痘（VV）病毒之间的高度相似性，此类药物也可能有效治疗可能出现的疫苗接种后并发症。开发一种安全有效的传染性软疣（MCV）治疗方法也将对公共卫生有益，MCV是另一种感染人类并导致长期皮肤病变的痘病毒，这些皮肤病变令人不舒服，有点毁容，并具有传染性。该提案是根据PAR-02-026提交的，该提案要求学术实验室和商业实体之间建立伙伴关系。PI是一位成熟的痘病毒学家;工业合作伙伴CEPTYR，Inc.是一家生物技术公司，其药物发现计划专门专注于蛋白磷酸酶。牛痘双特异性磷酸酶VH 1对病毒感染性至关重要，因此证实痘病毒磷酸酶是药物靶点。该提案的具体目标是：目标1：通过高通量筛选小分子化合物文库，鉴定天花磷酸酶和传染性软疣磷酸酶的小分子抑制剂。这些抑制剂将具有低μ M范围内的IC 50值，并且将另外通过专为该酶家族设计的一系列二级测定。目的2：先导化合物优化：开发具有改进的化学性质、效力和生物活性的小分子抑制剂。我们将应用有机化学的迭代轮次来增加目标1中分离的化合物的效力、选择性和生物利用度。化合物将在生化和细胞试验中进行检测。在细胞测定中显著影响病毒感染性的化合物将具有在动物模型中研究和进一步开发人类治疗剂的高潜力。

DESCRIPTION (provided by applicant): The reemergence of smallpox by release of variola virus, which was declared to be eradicated as a natural threat to humans in the late 1970s, is one of the most feared bioterrorist scenarios. Therefore, there is a strong need to develop potent antiviral therapeutics that would be easily administered to exposed individuals and would curtail or eliminate the development and spread of the disease. Because of the high degree of similarity between variola (VAR) and vaccinia (VV) viruses, such drugs are also likely to be efficacious in the treatment of post-vaccination complications that may arise. It would also be of public health benefit to develop a safe and efficacious treatment for Molluscum contagiosum (MCV), another poxvirus that infects humans and causes long-Iived skin lesions that are uncomfortable, somewhat disfiguring, and contagious. This proposal is being submitted in response to PAR-02-026, which requires a partnership between an academic laboratory and a commercial entity. The PI is an established poxvirologist; the industrial partner, CEPTYR, Inc. is a biotechnology company whose drug discovery programs are focused exclusively on protein phosphatases. The vaccinia dual specificity phosphatase VH1 is essential for viral infectivity, thus validating poxvirus phosphatases as drug targets. The specific aims of the proposal are: AIM 1: Identification of small molecule inhibitors of the variola phosphatase and the Molluscum contagiosum phosphatase through high-throughput screening of a small molecule chemical compound library. These inhibitors will have IC50 values in the low mu M range and will additionally pass a battery of secondary assays specifically designed for this family of enzymes. AIM 2: Lead optimization: development of small molecule inhibitors with improved chemical properties, potency, and biological activity. We will apply iterative rounds of organic chemistry to increase the potency, selectivity and bioavailability of the compounds isolated in Aim 1. Compounds will be tested in both biochemical and cellular assays. Compounds that significantly affect viral infectivity in cellular assays will have high potential for study in animal models and for further development to human therapeutics.