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靶向宿主的抗病毒治疗药物，能够单独使用或与其他可用药物联合使用，治疗多种NIAID新出现和再出现的优先病原体病毒。计划的活动范围横跨转化开发范围：从产生新的宿主目标导向，到验证有前途的先导分子，以及推进优化的先导。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)人类单倍体基因筛选可以识别多种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，也可以作为针对已鉴定基因的开发候选物；2)一套新的计算方法可以识别对主要药物靶点具有亲和力的化合物，从而产生基于中毒必需寡聚病毒或病毒-宿主蛋白复合物的新的抗病毒疗法；3)最近对干扰素如何与受体结合并转导其抗病毒基因表达程序的机制基础的见解可以用于开发具有新型抗病毒特性的干扰素，并且PDE12 2'磷酸二酯酶（a -74528）的独特小分子抑制剂可以延长这些新型和目前批准的干扰素（ifn）产生的抗病毒程序；4) RNA病毒对PI4P和pi4,5二磷酸（PIP2）等特定细胞内磷酸肌苷的广泛依赖可以通过开发合适的PI4-和PIP5-激酶的小分子抑制剂转化为有效的宿主细胞抗病毒治疗；5)通过重新利用现有已批准的药物，可以加速开发针对RNA病毒的新对策，并且高通量（HT）分子测量的同一类型的荟萃分析已经发现了治疗移植排斥和脂肪肝的新机会，可以应用于传染病，从而产生识别新宿主的管道

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