Targeting host 3'-5' exonucleases required for flaviviral infection

靶向黄病毒感染所需的宿主 3-5 核酸外切酶

• 批准号: 8540496
• 负责人: Mariano A. Garcia-Blanco
• 金额: $ 16.91万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8540496
• 关键词: Address; Arthropods; Biochemical; Biological Assay; Cell physiology; Cells; Culicidae; Dengue; Dengue Virus; Development; Drug Delivery Systems; Ensure; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Exonuclease; Flavivirus; Foundations; Growth; Human; Infection; Integration Host Factors; Lassa fever virus; Lead; Molecular; Open Reading Frames; Pharmaceutical Preparations; Phosphodiesterase I; Public Health; Reaction; Readiness; Recombinants; Risk; SARS coronavirus; Saccharomyces cerevisiae; Scheme; Screening procedure; Staging; System; Testing; Time; Viral; Virginia; Virus; Work; Yeasts; arm; base; biodefense; cell growth; drug discovery; experience; functional genomics; helicase; high throughput screening; human disease; in vitro Assay; in vivo; inhibitor/antagonist; novel; prevent; programs; restoration; small molecule

Arthropod-borne flaviviruses, and especially dengue viruses, cause a wide range of important human diseases for which there are no specific therapies. To address this critical shortfall in preparedness to confront these emerging and re-emerging viruses we have established a program to investigate host factors as targets of anti-dengue therapy. We have discovered many novel drug targets using functional genomics and en masse biochemical approaches. Among these are the 3'-5' exonucleases of the DnaQ/DEDDh superfamily of enzymes: EXD2, WRN and ERI3 (PRNPIP)). These enzymes are highly related to virally encoded exonucleases in SARS coronavirus and Lassa fever virus suggesting that the DnaQ/DEDDh superfamily of enzymes is widely used by pathogenic viruses and thus inhibitors of these enzymes could have broad spectrum of activity. We propose to characterize these enzymes in detail and to identify compounds that inhibit their activity and dengue infection. This will be achieved by 1) Developing in vitro assays for EXD2, WRN and ERI3 and 2) developing in vivo (yeast-based) assays to screen inhibitors of EXD2, WRN and ERI3. Significance to public health. Flaviviruses, and especially dengue virus, are an emerging threat to public health in the US, a current risk to our armed forces and other citizens deployed around the world, and a major problem globally. At this time there is little that can be done to prevent or treat the majority of flaviviral infections and therefore development of anti-flaviviral drugs is of crucial importance.

节肢动物传播的黄病毒，特别是登革热病毒，导致广泛的重要人类 没有特效药的疾病。为了解决这一严重的防备不足 为了对抗这些新出现的和重新出现的病毒，我们建立了一个程序来调查 宿主因素作为抗登革热治疗的靶点。我们已经发现了许多新的药物靶点 功能基因组学和整体生化方法。其中包括3‘-5’ DNAQ/DEDDh超家族酶：exd2、WRN和ERI3的核酸外切酶(PRNPIP))。这些 SARS冠状病毒和拉沙热中的酶与病毒编码的核酸外切酶高度相关 病毒提示DNAQ/DEDDh超家族酶被病原病毒广泛使用 因此，这些酶的抑制剂可能具有广泛的活性。我们建议 详细描述这些酶的特性，并确定抑制其活性和登革热的化合物 感染。这将通过以下方式实现：1)开发exd2、WRN和ERI3的体外检测方法 开发体内(基于酵母)的检测方法来筛选exd2、WRN和ERI3的抑制剂。 对公众健康的重要意义。黄病毒，特别是登革热病毒，是一种新的威胁 美国的公共卫生，目前对我们的武装部队和部署在美国各地的其他公民来说是一个威胁 世界，也是一个全球性的重大问题。在这个时候，几乎没有什么办法可以预防或治疗 大多数黄病毒感染，因此抗黄病毒药物的开发至关重要 重要性。