Identification of compounds that activate interferon to treat viral infections

描述(申请人提供)：先天免疫反应是抵御病毒感染的第一道屏障，并提供形成适当免疫反应所需的初始信号。干扰素(干扰素)是天然免疫系统的关键成分，是目前治疗多种病毒感染的有效药物。然而，对于没有疫苗可用的高致病性病毒或对病毒抑制剂具有抗药性的病毒株，特别需要新的抗病毒药物。由于干扰素反应诱导细胞抗病毒状态，从而防止病毒复制，诱导和/或激活干扰素反应的化合物将成为治疗病毒感染的令人兴奋的候选药物。这项应用旨在识别干扰素诱导的小分子化合物，用于治疗广泛的病毒感染和其他与干扰素相关的人类疾病。这些干扰素诱导化合物还可以用作病毒疫苗的免疫调节剂和/或佐剂，说明它们对人类健康的直接和重大影响。我们将使用一种新颖、简单和敏感的基于细胞的分析方法来鉴定诱导和/或激活先天免疫反应的化合物。为了实现这一目标，我们将：开发和调整一种基于细胞的分析方法，以确定诱导和/或激活天然免疫反应的化合物(目标1)。具体地说，我们将筛选两个结构多样化的小分子化合物文库，以证明我们的基于细胞的分析转换为自动化高通量筛选(HTS)格式的可行性。接下来，我们将使用二次化验来验证已识别的HITS及其生物学相关性(目标2)。我们将通过二次检测将初步筛选中的活性化合物鉴定为阳性，评估它们的物种特异性、作用机制和毒性，以便在抗病毒检测中优先确定它们的特征。我们简单的基于细胞的分析是一种全面可靠的方法，可以立即确定有前景的干扰素调节剂，用于治疗病毒感染和其他依赖干扰素独特用途的人类疾病。该项目将使我们能够实现我们的长期目标，即在临床前动物模型中展示已识别的化合物的抗病毒特性，以选择主要的候选治疗方案。 公共卫生相关性：非常需要新的抗病毒药物，特别是针对尚无疫苗可用的高致病性病毒或对病毒抑制剂产生抗药性的病毒株。由于干扰素(干扰素)反应在细胞中诱导抗病毒状态，从而防止病毒复制，因此增强或激活干扰素反应的化合物是作为抗病毒药物、疫苗佐剂或潜在免疫调节剂的主要候选药物。利用我们的高通量细胞分析，我们将鉴定干扰素调节化合物，这些化合物将代表治疗病毒感染和其他依赖干扰素独特用途的人类疾病的有前途的疗法。

DESCRIPTION (provided by applicant): The innate immune response represents the first barrier against viral infections and provides the initial signal required for development of an appropriate immune response. Interferon (IFN) constitutes a critical element of the innate immune system and is a current therapeutic agent that is effective against a broad spectrum of viral infections. However, new antiviral drugs are particularly needed for highly pathogenic viruses for which no vaccine is available or for virus strains resistant to viral inhibitors. Because the IFN response induces a cellular antiviral state that prevents virus replication, compounds that induce and/or activate the Interferon response will represent exciting candidates as therapeutics to treat viral infections. This application aims to identify interferon-inducing small molecule compounds for the treatment of a broad spectrum of viral infections and other interferon-related human diseases. These interferon-inducing compounds could be also used as immunomodulators and/or adjuvants for viral vaccines, illustrating their immediate and significant impact on human health. We will use a novel, simple, and sensitive cell-based assay to identify compounds that induce and/or activate the innate immune response. To achieve this, we will: develop and adapt a cell-based assay to identify compounds that induce and/or activate the innate immune response (Aim 1). Specifically, we will screen two libraries of structurally diverse small molecule compounds to demonstrate the feasibility of our cell-based assay to be translated to automated high-throughput screening (HTS) format. Next, we will use secondary assays to validate identified hits and their biological relevance (Aim 2). We will certify the compounds active in the primary screen as positive hits by secondary assays, evaluating their species specificity, mechanism of action and toxicity in order to prioritize their characterization in antiviral assays. Our straightforward cell-based assay represents a comprehensive and reliable approach for the immediate identification of promising IFN modulators to treat viral infections and other human diseases that rely on the unique use of IFN. This project will allow us to reach our long term goals of demonstrating the antiviral properties of the identified compounds in preclinical animal models to select lead therapeutic candidates. PUBLIC HEALTH RELEVANCE: There is a great need for new antiviral drugs, particularly against highly pathogenic viruses for which no vaccine is yet available or virus strains that become resistant to viral inhibitors. Because the interferon (IFN) response induces an antiviral state in cells that prevents virus replication, compounds that enhance or activate the IFN response represent lead candidates as antivirals, vaccine adjuvants, or potential immunomodulators. Using our high throughput cell-based assay, we will identify IFN-modulating compounds that will represent promising therapeutics to treat viral infections and other human diseases that rely on the unique use of IFN.