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物对抗耐药性该项目的总体目标是引领一种创新的小分子抗病毒战略，旨在对抗该领域迅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以宿主细胞因子为靶点，而不是直接以病毒成分为靶点，将产生一种显著的障碍，防止自发地摆脱抑制。个别病毒突变很可能无法完全恢复或取代对病毒传播至关重要的被抑制的宿主因子的功能。由于相关病毒家族的成员通常依赖一组重叠的宿主成分，预计这些抑制剂的靶标范围将会扩大。后者是在筛选工作中确定合适的候选化合物的一个容易获得的标记。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，从而减少了与药物有关的副作用的可能发展。粘病毒被选为未达到目标的原因有三个：(1)流感病毒等粘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会导致急性疾病；(3)不同的粘病毒之间的病原生物学基础是保守的。为了验证这种抗粘病毒策略的可行性，对大规模高通量抗麻疹病毒药物筛选进行了分析，以寻找目标范围更广的HITS。除其他外，这又回到了一种极具效力(纳摩尔范围)的新型化合物类别，对不同的正粘病毒和副粘病毒具有广泛的抑制作用，包括甲型流感病毒、人类副流感病毒、麻疹病毒和腮腺炎病毒。这类化合物的进一步开发要求对其抗病毒作用(目标1)进行机械性表征，并进行点击到领先的化学优化。目前的先导和优化的类似物将接受ADME试验性评估，并使用流感病毒感染的小动物模型进行体内毒性和有效性测试(目标2)。将通过与传统的病毒特异性抑制剂相比，尝试使选定的粘病毒适应在粘病毒抑制剂类别存在下的生长来评估自发病毒逃脱抑制的相对频率，从而评估这一抗病毒策略对抗新出现的耐药性的长期潜力(目标3)。 与公共卫生相关：粘病毒家族含有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，这些病毒是人类的主要病原体。对特许流感药物的新耐药性、高致病性流感毒株大流行的威胁、副流感病毒疫苗的缺乏以及流行性腮腺炎和麻疹病毒的重新出现，要求开发创新的粘病毒疗法来抵消耐药性。

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.