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

节肢动物传播的黄病毒，特别是登革病毒，引起广泛的重要人类免疫缺陷。 没有特效疗法的疾病。为了解决这一严重的准备不足， 为了应对这些新出现和重新出现的病毒，我们建立了一个项目， 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， 功能基因组学和生物化学方法。其中有3 '-5' DnaQ/DEDDh酶超家族的外切核酸酶：EXD 2、WRN和ERI 3（PRNPIP））。这些 酶与SARS冠状病毒和拉沙热中病毒编码的核酸外切酶高度相关 这表明DnaQ/DEDDh超家族酶被致病病毒广泛使用 因此这些酶的抑制剂可以具有广谱活性。我们建议 详细描述这些酶的特征，并鉴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EXD 2、WRN和ERI 3的体外试验; 2） 开发体内（基于酵母的）测定以筛选EXD 2、WRN和ERI 3的抑制剂。 对公共卫生的重要性。黄病毒，特别是登革热病毒，是一种新兴的威胁， 公共卫生在美国，目前的风险，我们的武装部队和其他公民部署在各地， 这是一个世界性的问题，也是一个全球性的问题。在这个时候，几乎没有什么可以做，以防止或治疗， 大多数黄病毒感染，因此开发抗黄病毒药物至关重要 重要性

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.