Advancing Broad Spectrum Host-Targeting Antiviral Strategies to the Clinic

说明)：我们中心的总体主题和目标是发展新的班级 能够治疗多发性新城疫的宿主靶向抗病毒疗法 优先病原体病毒，单独使用或与其他可用制剂联合使用时。的范围 规划的活动跨越翻译开发范围：从生成专注于新的主机目标 铅，以验证有前途的铅分子，并推进优化的线索。我们假设一个 令人兴奋的初步数据集的集合现在提供了协作转换为 新型广谱抗病毒药物的开发。更具体地说，我们将检验以下假设：1) 人类单倍体遗传筛选可以识别多种RNA病毒所需的新宿主基因，并且 重组AAV病毒载体既可以验证这些靶点，又可以作为开发候选靶点 2)一套新的计算方法可以识别具有亲和力的化合物 主导药物靶点，从而产生基于中毒基本寡聚病毒的新的抗病毒疗法 或病毒-宿主蛋白复合体；3)对干扰素如何参与其 受体及其转导抗病毒基因表达程序可被杠杆作用于 干扰素具有新的抗病毒特性，以及一种独特的PDE12‘磷酸二酯酶小分子抑制剂 (A-74528)可以延长由这些新的和目前产生的抗病毒程序 批准的干扰素(IFN)；4)RNA病毒对特定细胞内的明显广泛依赖 如PI4P和PI4，5-二磷酸(PIP2)等磷脂酰肌醇可以转化为有效的 通过开发适当的特异性PI4-小分子抑制剂进行基于宿主细胞的抗病毒治疗 和pips-kinase；5)可以加快针对rna病毒的新对策的开发。 通过对现有已批准药物的再利用，以及同一类型的高通量荟萃分析 (HT)分子测量发现了治疗移植排斥反应和 脂肪肝可以应用于传染病，从而产生一条识别新宿主靶点的管道 病毒依赖的，可以用批准的药物抑制的；6)考虑的治疗方法 以上两种药物联合使用，可获得更有效、更广谱的抗病毒疗法。 抵抗的障碍。

instructions): Our Overall theme and objective of this Center is to develop new classes of host-targeting antiviral therapeutics that are capable of treating multiple NIAID Emerging and Re-emerging Priority Pathogen viruses, when used alone or in combination with other available agents. The range of planned activities spans the translational development spectrum: from generating new host target focused leads, to validating promising lead molecules, and advancing optimized leads. We hypothesize that a collection of exciting preliminary datasets now offer the potential to be collaboratively translated into the development of novel broad spectrum antivirals. More specifically, we will test the following hypotheses: 1) human haploid genetic screens can identify novel host genes required for multiple RNA viruses, and recombinant AAV viral vectors can both validate these targets and serve as development candidates against the identified genes; 2) a suite of novel computational methods can identify compounds with affinity for dominant drug targets and thereby yield new antiviral therapies based on poisoning essential oligomeric viral or viral-host protein complexes; 3) recent insights into the mechanistic basis of how interferons engage their receptors and transduce their antiviral gene expression program can be leveraged into the development of interferons with novel antiviral properties, and that a unique small molecule inhibitor of PDE12 2' phosphodiesterase (A-74528) can prolong the antiviral programs generated by both these novel and currently approved interferons (IFNs); 4) the apparent widespread dependence of RNA viruses on specific intracellular pools of phosphoinositides such as PI4P and PI4,5 bisphosphate (PIP2) can be translated into an effective host cell based antiviral therapy via the development of appropriate small molecule inhibitors of specific PI4- and PIPS- kinases ; 5) the development of novel countermeasures against RNA viruses can be accelerated through repurposing of existing approved drugs, and that the same type of meta-analysis of high throughput (HT) molecular measurements that has uncovered new opportunities for treating transplant rejection and fatty liver can be applied to infectious diseases and thereby yield a pipeline for identifying novel host targets upon which viruses depend and that can be inhibited with approved drugs; 6) the therapeutics contemplated above can be used in combination to achieve still more potent, broad-spectrum antiviral therapies with high barriers to resistance.