Host-Directed Inhibitors of Myxovirus Replication

本项目的总体目标是开发粘病毒复制的宿主定向抑制剂，旨在将流行的单药、单虫抗病毒治疗方法转变为单药、多虫模式。这种开创性的方法旨在系统地解决两个主要的挑战，经常与病毒治疗：预先存在的或快速发展的耐药性的抑制剂，和一个狭窄的适应症谱的许多抗病毒药物，这是加剧了成本和低灵活性的当前制药工艺，病毒进化和出现的新的，高致病性的代理。我们假设这些障碍可以通过治疗靶向病毒繁殖所需的宿主细胞途径来克服，因为单个病毒突变可能无法补偿宿主途径的功能丧失，并且相关家族的病毒通常依赖于重叠的宿主组分来完成其生命周期。考虑到与宿主导向方法内在相关的药物诱导副作用的可能性较高，主要与急性疾病相关的粘病毒科病原体（如流感病毒、尼帕病毒和呼吸道合胞病毒）特别适合这种治疗策略，因为治疗时间以及宿主对药物的暴露仍然有限。 为了满足未来抗病毒治疗的临床需求，该项目将建立在我们已建立的抗粘病毒项目提供的坚实基础上，并追求创新小分子抗病毒药物的鉴定和分子表征，为未来确认的治疗候选状态向IND申报状态的发展奠定坚实的基础。通过自动化筛选和化学精细化的结合，我们的项目先前已经确定了一个小分子命中池，其具有针对流感病毒和副粘病毒家族成员的扩大的纳摩尔至低微摩尔活性。在这个补充项目中，将坚持一系列明确定义的里程碑，将实施一种新颖的、创新的双重粘病毒病原体筛选方案，以进一步多样化现有的粘病毒抑制剂组合，减轻早期失败的风险（目标1）。为了寻找满足这些里程碑并保证进一步开发的结构多样的先导支架的子集，将针对不同的细胞系和原代细胞组确定新发现的和现有的命中的活性浓度，对暴露细胞的作用概况，评估病毒复制中的停滞点，并且对于具有最高抗病毒效力的选定先导，更广泛的病原体指示谱，分子靶标，并确定关键ADME性质（目标2）。这些练习的目标是确定一种主要支架和至少一种结构无关的替代品，适用于合成开发和临床前评估。

It is the overarching goal of this project to develop host-directed inhibitors of myxovirus replication that are designed to transform the prevalent one-drug, one-bug approach of antiviral therapy to a one-drug, multiple-bugs paradigm. This pioneering approach aims to systemically address two major challenges frequently associated with viral therapeutics: pre-existing or rapidly developing resistance to the inhibitor, and a narrow indication spectrum of many antiviral drugs, which are aggravated by cost and low flexibility of the current pharmaceutical manufacturing process, viral evolution and the emergence of novel, highly pathogenic agents. We hypothesize that these obstacles can be overcome through therapeutic targeting of host cell pathways required for virus propagation, since individual viral mutations will likely not compensate for loss-of-function of a host pathway, and viruses of related families frequently depend on overlapping sets of host components for completion of their life cycle. Considering a higher potential for drug-induced side effects that is intrinsically associated with a host-directed approach, pathogens of the myxovirus families such as influenza virus, Nipah virus and respiratory syncytial virus that are predominantly associated with acute disease emerge as particularly suitable for this therapeutic strategy, since treatment time and thus host exposure to the drug remain limited. To meet future clinical needs of antiviral therapy, this project will build on the solid foundation provided by our established anti-myxovirus program and pursue the identification and molecular characterization of innovative small-molecule antivirals to establish a tangible foundation for the future development of confirmed therapeutic candidate status towards IND-filing status. Through a combination of automated screening and chemical elaboration, our program has previously identified a pool of small-molecule hits with broadened nanomolar to low-micromolar activity against influenza virus and members of the paramyxovirus family. In this supplement project that will adhere to a set of clearly defined milestones, a novel, innovative dual-myxovirus pathogen screening protocol will be implemented to further diversify the portfolio of existing myxovirus inhibitors, alleviating the risk of early stage failure (aim 1). In search of a subset of structurally diverse lead scaffolds that meet these milestones and warrant further development, active concentrations of newly discovered and existing hits will be determined for a diverse panel of cell lines and primary cells, the effect on exposed cells profiled, the point-of-arrest in virus replication assessed, and, for selected leads with the highest antiviral potency, the broader pathogen indication spectrum, molecular target, and key ADME properties determined (aim 2). It is the goal of these exercises to identify a lead scaffold and at least one structurally unrelated alternative suitable for synthetic development and pre-clinical assessment.