Counteracting Resistance through Host-Directed Myxovirus Inhibitors

描述（由申请人提供）：通过宿主导向的粘病毒抑制剂抵消耐药性本项目的总体目标是带头创新的小分子抗病毒策略，旨在抵消该领域迅速出现的病毒耐药性。该方法是由以下假设驱动的：在病毒生命周期中靶向宿主细胞因子而不是直接靶向病毒组分将产生针对自发逃避抑制的显著屏障。单个病毒突变可能无法完全恢复或取代病毒繁殖所必需的受抑制宿主因子的功能。由于相关病毒家族的成员通常依赖于一组重叠的宿主组分，因此预期这些抑制剂的靶向范围会扩大。后者构成了一个容易获得的标记，以确定合适的候选化合物在筛选工作。与急性而非慢性疾病相关的病原体似乎是这种治疗方法特别理想的靶点，因为治疗时间以及因此宿主对药物的暴露保持有限，从而减少了药物相关副作用的可能发展。由于三个原因，粘病毒被选择为未满足的目标：（1）粘病毒如流感病毒是对人类健康的主要威胁;（2）绝大多数人类粘病毒感染导致急性疾病;（3）病原体生物学的基本原理在不同的粘病毒之间是保守的。为了测试这种抗粘病毒策略的可行性，分析了大规模高通量抗麻疹病毒药物筛选中具有加宽靶范围的命中。其中，这已经返回了一种具有广泛抑制不同的正粘病毒和副粘病毒（包括甲型流感病毒、人副流感病毒、麻疹病毒和腮腺炎病毒）的强效（纳摩尔范围）新型化合物类别。这类化合物的进一步开发要求其抗病毒作用的机制表征（目的1）和命中-铅化学优化。目前的先导和优化的类似物将进行试点ADME评估和体内毒性和疗效测试，使用流感病毒感染的小动物模型（目的2）。通过与常规病毒特异性抑制剂相比，尝试在存在粘病毒抑制剂的情况下使选定的粘病毒适应生长，评估自发病毒逃避抑制的相对频率，从而评估这种抗病毒策略抵消新出现耐药性的长期潜力（目的3）。 公共卫生相关性：粘病毒家族包含RNA病毒，如流感病毒、呼吸道合胞病毒、副流感病毒、腮腺炎病毒和麻疹病毒，它们构成了主要的人类病原体。对许可的流感药物的新出现的耐药性、高致病性流感毒株大流行的威胁、缺乏针对副流感病毒的疫苗以及腮腺炎和麻疹病毒的重新出现，要求开发对抗耐药性的创新性粘病毒疗法。

DESCRIPTION (provided by applicant): Counteracting Resistance through Host-Directed Myxovirus Inhibitors It is the overall goal of this project to spearhead an innovative small-molecule antiviral strategy that is designed to counteract the rapid emergence of viral resistance in the field. The approach is driven by the hypothesis that targeting host cell factors in the viral life cycle rather than direct targeting of viral components will create a significant barrier against spontaneous escape from inhibition. Individual viral mutations will likely fail to fully restore or replace functionality of an inhibited host factor that is essential for virus propagation. Since members of related viral families typically rely on an overlapping set of host components, a broadened target range of these inhibitors is expected. The latter constitutes a readily accessible marker to identify suitable candidate compounds in screening exercises. Pathogens associated with acute, rather than chronic, disease appear particularly desirable targets for this therapeutic approach since treatment time, and thus host exposure to the drug, is kept limited, thereby reducing the possible development of drug-related side effects. Myxoviruses have been chosen as an unmet target for three reasons: (1) myxoviruses such as influenza virus are a major threat to human health; (2) the vast majority of human myxovirus infections result in acute disease; (3) fundamentals of pathogen biology are conserved between different myxoviruses. To test the feasibility of this anti-myxovirus strategy, a large-scale high-throughput anti-measles virus drug screen was analyzed for hits with broadened target range. This has returned, among others, an exquisitely potent (nanomolar range) novel compound class with broad-range inhibition of different ortho- and paramyxoviruses including influenza A virus, human parainfluenzaviruses, measles virus and mumps virus. Further development of this compound class mandates mechanistic characterization of its antiviral effect (aim 1) and hit-to-lead chemical optimization. The current lead and optimized analogs will be subjected to pilot ADME assessment and in vivo toxicity and efficacy testing, using a small-animal model of influenza virus infection (aim 2). The relative frequency of spontaneous viral escape from inhibition and thus the long-term potential of this antiviral strategy to counteract emerging resistance will be assessed through attempts to adapt selected myxoviruses to growth in the presence of the myxovirus inhibitor class in comparison with conventional, virus-specific inhibitors (aim 3). PUBLIC HEALTH RELEVANCE: The myxovirus families contain RNA viruses such as influenza virus, respiratory syncytial virus, parainfluenza viruses, mumps virus and measles virus, which constitute major human pathogens. Emerging resistance against licensed influenza drugs, the threat of a pandemic of highly pathogenic influenza strains, lack of vaccines against parainfluenza viruses, and re-emergence of mumps and measles virus mandate the development of innovative myxovirus therapeutics that counteract resistance.