Developing Myxovirus Inhibitors with Expanded Pathogen Target Range

描述（由申请人提供）：本项目的总体目标是率先采用新型治疗策略，旨在将传统的单药、单虫抗病毒治疗方法转变为单药类、多虫模式。这是由于认识到当前制药技术的高成本和缺乏灵活性、病毒的持续进化和新型病毒病原体的出现需要提高药物发现和开发过程的灵活性。本项目选择了粘病毒科的病原体，因为粘病毒如流感病毒、副流感病毒、呼吸道合胞病毒和麻疹病毒是对人类健康的主要威胁，并且病原体生物学的许多基本原理在不同的粘病毒科成员之间是保守的。为了应对未来抗病毒治疗的临床挑战，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，并在两个互补但独立的途径中开发具有更广泛抗粘病毒靶谱的创新小分子抗病毒药物。一类新型麻疹病毒RNA依赖性RNA聚合酶（RdRp）抑制剂将通过药效团提取和基于结构的支架工程或设计转化为柔性抗副粘病毒平台。与此同时，将采用宿主定向抗粘病毒方法，阻断病毒复制所需的宿主途径。第一种方法源于我们团队开发的麻疹病毒聚合酶（L）蛋白的治疗候选阻断剂。受抑制剂靶位点的空间组织是 在相关的副粘病毒L蛋白中很大程度上是保守的，光反应性类似物将被用作创新的分子探针，以优化在共结晶的初步研究中鉴定的有折叠能力的L片段。分子药效团的提取将使这种病毒特异性支架能够通过针对相关L靶标的计算机设计结合化学合成和生物测试转化为多功能抗副粘病毒平台（目的1）。平行的方法基于这样的假设，即由于相关病毒家族依赖于一组相似的宿主因素，因此宿主定向抗病毒药物显示出更宽的病原体靶谱。我们的计划已经确定了纳摩尔流感和副粘病毒阻断剂类与主机定向配置文件，低毒性和良好的药代动力学。该支架将被完全机械地表征，并确定其宿主靶标。此外，一个新的，创新的高通量筛选协议和数据挖掘的系统范围内的主机流感相互作用屏幕将被实施，以确定独立的主机目标和多样化的主机定向命中组合（目标2）。随着项目的进展，立即从试点研究中已经确定的先导化合物开始，并补充新发现的有希望的命中物，将综合推进先导化合物候选物的药物样性质，确定选择的ADME性质，并确定药代动力学，小动物疗效和生物毒性（目标3）。

DESCRIPTION (provided by applicant): It is the overarching goal of this project to spearhead novel therapeutic strategies that are designed to transform the traditional one-drug, one-bug approach of antiviral therapy to a one-drug class, multiple-bugs paradigm. This is driven by the realization that high cost and lack of flexibility of current pharmaceutical manufacturing technologies, continuous viral evolution and the emergence of novel viral pathogens demand heightened flexibility of the drug discovery and development process. Pathogens of the myxovirus families have been chosen for this program because myxoviruses such as influenza virus, parainfluenza viruses, respiratory syncytial virus and measles virus are a major threat to human health, and many fundamentals of pathogen biology are conserved between different myxovirus family members. To meet future clinical challenges of antiviral therapy, this project will build on the solid foundation provided by our established anti- myxovirus program and pursue the development of innovative small-molecule antivirals with broadened anti- myxovirus target spectrum in two complementary, but independent avenues. A novel class of measles virus RNA-dependent RNA-polymerase (RdRp) inhibitors will be transformed into a flexible anti-paramyxovirus platform through pharmacophore extraction and structure-based scaffold engineering or design. In parallel, a host directed anti-myxovirus approach will be pursued that blocks host pathways required for virus replication. The first approach originates from a therapeutic candidate blocker of the measles virus polymerase (L) protein that was developed by our team. Driven by the hypothesis that the spatial organization of the inhibitor target site is largely conserved among related paramyxovirus L proteins, photoreactive analogs will be employed as innovative molecular probes to optimize a folding-competent L fragment identified in pilot studies for co- crystallization. Extraction of a molecular pharmacophore will enable the transformation of this virus-specific scaffold to a versatile anti-paramyxovirus platform through i silico design against related L targets in conjunction with chemical synthesis and biotesting (aim 1). The parallel approach rests on the hypothesis that host-directed antivirals show a broadened pathogen target spectrum due to dependence of related viral families on a similar set of host factors. Our program has identified a nanomolar influenza and paramyxovirus blocker class with host-directed profile, low toxicity and good pharmacokinetics. This scaffold will be fully mechanistically characterized and its host target determined. In addition, a novel, innovative high-throughput screening protocol and data-mining of system-wide host-influenza interaction screens will be implemented to identify independent host targets and diversify the host-directed hit portfolio (aim 2). Commencing immediately with the leads already identified in pilot studies and supplemented with newly discovered promising hits as the project progresses, drug-like properties of lead candidates will be synthetically advanced, select ADME properties determined and pharmacokinetics, small-animal efficacy, and biotoxicity determined (aim 3).