Counteracting Resistance through Host-Directed Myxovirus Inhibitors

描述（由申请人提供）：通过宿主导向的黏液病毒抑制剂对抗耐药性这个项目的总体目标是引领一种创新的小分子抗病毒策略，旨在对抗该领域快速出现的病毒耐药性。这种方法是基于这样一种假设，即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成分，将对抑制的自发逃逸产生重大障碍。单个病毒突变可能无法完全恢复或取代对病毒传播至关重要的被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成分，因此这些抑制剂的靶标范围有望扩大。后者构成一个容易接近的标记，以确定筛选练习中合适的候选化合物。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目标，因为治疗时间和宿主接触药物的时间都是有限的，从而减少了可能发生的药物相关副作用。选择黏液病毒作为未满足的目标有三个原因：(1)黏液病毒如流感病毒是对人类健康的主要威胁；(2)绝大多数人黏液病毒感染导致急性疾病；(3)不同黏液病毒之间病原生物学的基本原理是保守的。为了验证这种抗黏液病毒策略的可行性，我们对大规模的高通量抗麻疹病毒药物筛选进行了分析，以扩大靶标范围。这就产生了一种非常有效（纳摩尔范围）的新型化合物类，对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具有广泛的抑制作用。这类化合物的进一步发展需要对其抗病毒作用的机理进行表征（目标1），并进行靶向化学优化。目前的先导和优化的类似物将使用流感病毒感染的小动物模型进行ADME试点评估和体内毒性和功效测试（目标2）。与传统的病毒特异性抑制剂相比，将通过尝试使选定的黏液病毒适应黏液病毒抑制剂类存在下的生长，来评估病毒从抑制中自发逃逸的相对频率，以及这种抗病毒策略对抗新出现的耐药性的长期潜力（目的3）。

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.