Developing Myxovirus Inhibitors with Expanded Pathogen Target Range

描述(由申请人提供)：该项目的首要目标是引领新的治疗策略，旨在将传统的一种药物、一种细菌的抗病毒治疗方法转变为一种药物类别、多种细菌的范例。这是因为人们意识到，当前制药制造技术的高成本和缺乏灵活性、不断的病毒进化以及新的病毒病原体的出现，要求药物发现和开发过程具有更高的灵活性。由于流感病毒、副流感病毒、呼吸道合胞病毒和麻疹病毒等粘病毒是对人类健康的主要威胁，而且许多病原体生物学的基本原理在不同的粘病毒家族成员之间是保守的，因此本项目选择了粘病毒家族的病原体。为了迎接未来抗病毒治疗的临床挑战，该项目将建立在我们既定的抗粘病毒计划提供的坚实基础上，并在两个互补但独立的途径上继续开发具有扩大抗粘病毒靶谱的创新小分子抗病毒药物。一类新型的麻疹病毒RNA依赖的RNA聚合酶(RdRp)抑制剂将通过药效团的提取和基于结构的支架工程或设计转化为灵活的抗副粘病毒平台。同时，将采用以宿主为导向的抗粘病毒方法，以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)蛋白的治疗候选阻滞剂。由抑制剂靶点的空间组织是 在相关副粘病毒L蛋白中高度保守的光反应类似物将被用作创新的分子探针，以优化在初步研究中确定的具有折叠能力的L片段的共结晶。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靶标的电子设计，结合化学合成和生物测试(目标1)，转化为通用的抗副粘病毒平台。平行的方法基于这样的假设，即宿主导向的抗病毒药物由于相关病毒家族对一组相似的宿主因子的依赖而显示出更宽的病原体靶标光谱。我们的计划已经确定了一种具有宿主导向的、低毒和良好的药代动力学的纳米流感和副粘病毒阻滞剂。这个支架将被完全机械地表征，并确定其宿主目标。此外，将实施新颖、创新的高通量筛选协议和全系统主机-流感相互作用屏幕的数据挖掘，以确定独立的主机目标，并使以主机为导向的HIT组合多样化(目标2)。从试点研究中已经确定的先导化合物开始，随着项目的进展，补充新发现的有希望的药物，将综合提高候选先导药物的类药物特性，确定ADME特性，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).