Advancing Broad Spectrum Host-Targeting Antiviral Strategies to the Clinic

描述（由申请人提供）：本中心的总体主题和目标是开发新型宿主靶向抗病毒治疗药物，当单独使用或与其他可用药物联合使用时，能够治疗多种NIAID新发和再发优先病原体病毒。计划的活动范围涵盖了翻译开发范围：从生成新的宿主靶向先导化合物，到验证有前景的先导化合物分子，以及推进优化的先导化合物。我们假设，一组令人兴奋的初步数据集现在提供了合作转化为新型广谱抗病毒药物开发的潜力。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，并且重组AAV病毒载体既可以验证这些靶标又可以作为针对所鉴定基因的开发候选物;（二）一套新的计算方法可以识别出对主要药物靶点具有亲和力的化合物，从而产生基于中毒的新的抗病毒疗法。必需的寡聚病毒或病毒-宿主蛋白复合物; 3）最近对干扰素如何与其受体结合并抑制其抗病毒基因表达程序的机制基础的认识可以用于开发具有新的抗病毒特性的干扰素，一种独特的PDE 12 2'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批准的干扰素（IFN）产生的抗病毒程序; 4）RNA病毒对磷酸肌醇如PI 4P和PI 4的特异性细胞内库的明显广泛依赖性，5二磷酸（PIP 2）可以通过开发特异性PI 4-和PIP 5-激酶的适当小分子抑制剂而转化为有效的基于宿主细胞的抗病毒疗法; 5）可以通过重新利用现有批准的药物来加速针对RNA病毒的新对策的开发，并且已经发现治疗移植排斥和脂肪肝的新机会的高通量（HT）分子测量的相同类型的荟萃分析可以应用于感染性疾病，从而产生鉴定新宿主的管道 病毒依赖的靶点，并且可以用批准的药物抑制; 6）上述治疗剂可以组合使用，以获得更有效的、广谱的抗病毒治疗，具有高的耐药性屏障

DESCRIPTION (provided by applicant): 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 PIP5- 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