Inhibiting poxvirus phosphatases: therapy and biodefense

抑制痘病毒磷酸酶：治疗和生物防御

• 批准号: 6732090
• 负责人: Paula Traktman
• 金额: $ 74.74万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732090
• 关键词: Poxviridae; antiviral agents; bioterrorism /chemical warfare; cooperative study; drug design /synthesis /production; high throughput technology; phosphatase inhibitor

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.

描述（由申请人提供）：通过释放Variola病毒的天花再出现，该病毒被宣布在1970年代后期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，这些抗病毒药会很容易地用于暴露的个体，并减少或消除疾病的发展和传播。由于Variola（VAR）和Vaccinia（VV）病毒之间的相似性很高，因此此类药物也可能在治疗可能出现的疫苗接种并发症的治疗中有效。为软体动物（MCV）开发安全有效的治疗方法，这也是公共卫生的好处，这是另一种感染人类并引起长期降低皮肤病变的毒软病毒，这些疾病不舒服，有些脱落，有些脱落和传染性。该提案是针对PAR-02-026提交的，Par-02-026需要学术实验室与商业实体之间的合作关系。 PI是一位既定的痘病毒学家。工业合作伙伴Ceptyr，Inc。是一家生物技术公司，其药物发现计划仅专注于蛋白质磷酸酶。疫苗双重特异性磷酸酶VH1对于病毒感染性至关重要，因此验证痘病毒磷酸酶是药物靶标。该提案的具体目的是：目标1：通过对小分子化学化合物文库的高通量筛选，通过高通量筛选鉴定了Variola磷酸酶的小分子抑制剂和小软体动物contagiosum磷酸酶。这些抑制剂将在低MU M范围内具有IC50值，并通过专门为该酶家族设计的一系列次要测定。 AIM 2：铅优化：具有改善化学特性，效力和生物活性的小分子抑制剂的开发。我们将应用有机化学的迭代回合，以提高AIM 1中分离的化合物的效力，选择性和生物利用度。将在生化和细胞测定中测试化合物。在细胞测定中显着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发展到人类疗法的高潜力。