Advancing Broad Spectrum Host-Targeting Antiviral Strategies to the Clinic

说明）：我们的总体主题和这个中心的目标是开发新的类 能够治疗多发性NIAID新发和再发的宿主靶向抗病毒治疗剂 优先病原体病毒，单独使用或与其他可用药物联合使用。的范围 计划中的活动涵盖了翻译开发范围：从生成新的主机目标， 导致，验证有前途的铅分子，并推进优化的铅。我们假设 一系列令人兴奋的初步数据集现在提供了合作转化为 开发新型广谱抗病毒药物。更具体地说，我们将测试以下假设：1） 人类单倍体遗传筛选可以鉴定多种RNA病毒所需的新宿主基因， 重组AAV病毒载体既可以验证这些靶标，又可以作为开发候选物， 2）一套新的计算方法可以识别出对以下物质具有亲和力的化合物： 优势药物靶点，从而产生新的抗病毒疗法的基础上中毒的基本寡聚病毒 或病毒-宿主蛋白复合物; 3）最近对干扰素如何参与其 它们的抗病毒基因表达程序可以用于开发 具有新的抗病毒特性的干扰素，以及PDE 12 2'磷酸二酯酶的独特小分子抑制剂 （A-74528）可以延长这些新的和目前的抗病毒程序 批准的干扰素（IFN）; 4）RNA病毒对特异性细胞内干扰素的明显广泛依赖 磷酸肌醇如PI 4P和PI 4，5二磷酸（PIP 2）的库可以被翻译成有效的 基于宿主细胞的抗病毒治疗，通过开发适当的特异性PI 4- 和PIPS-激酶; 5）可以加速针对RNA病毒的新对策的开发 通过重新利用现有的已批准的药物，并且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的新机会， 脂肪肝可以应用于感染性疾病，从而产生用于鉴定新的宿主靶点的管道 病毒依赖于这些药物，并且可以用批准的药物抑制这些药物; 6）所考虑的治疗剂 以上所述的化合物可以联合使用，以获得更有效的广谱抗病毒治疗， 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.