Inhibiting poxvirus phosphatases: therapy and biodefense

描述(申请人提供)：通过释放天花病毒重新出现天花，这种病毒在1970年代末被宣布作为对人类的自然威胁而被根除，这是最令人恐惧的生物恐怖情景之一。因此，迫切需要开发有效的抗病毒疗法，这种疗法很容易对暴露于病毒的个人进行管理，并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，这种药物在治疗可能出现的疫苗接种后并发症方面也很可能有效。开发一种安全有效的治疗传染性软骨病(MCV)的方法也将有利于公众健康。MCV是另一种感染人类的痘病毒，会导致长期存活的皮肤损害，令人不适，有些毁容，并具有传染性。本提案是根据PAR-02-026提出的，该提案要求学术实验室和商业实体之间建立伙伴关系。PI是一位著名的痘病毒学家；其工业合作伙伴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质磷酸酶。痘苗病毒双特异性磷酸酶VH1对病毒的感染性是必不可少的，从而验证了痘病毒磷酸酶作为药物靶点的有效性。该提案的具体目的是：目的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。这些抑制剂的IC50值将在低MUM范围内，并将额外通过专门为该酶家族设计的一系列二次检测。目标2：先导优化：开发具有更好的化学性质、效力和生物活性的小分子抑制剂。我们将应用反复的有机化学循环，以提高在目标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分析中进行测试。在细胞检测中显著影响病毒感染性的化合物将具有很高的动物模型研究潜力，并有可能进一步发展为人类疗法。

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.