Identification of compounds that activate interferon to treat viral infections

鉴定激活干扰素以治疗病毒感染的化合物

• 批准号: 8181991
• 负责人: Luis Martinez-Sobrido
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181991
• 关键词: Adjuvant; Affect; Animal Model; Antiviral Agents; Autoimmunity; Biological; Biological Assay; Cell Line; Cells; Clinic; Communicable Diseases; Community Health; Dependence; Dermatitis; Development; Disease; Disease Outbreaks; Dose; Drug Delivery Systems; Elements; Embryo; Epithelial; Firefly Luciferases; Fluorescence Microscopy; Generations; Genes; Goals; Health; Human; Immune response; Immune system; Immunomodulators; Insulin-Dependent Diabetes Mellitus; Interferon Type I; Interferons; Kidney; Lead; Libraries; Malignant Neoplasms; Metric; Monitor; Multiple Sclerosis; Pathway interactions; Performance; Pharmaceutical Preparations; Procedures; Property; Proteins; Reader; Reporter; Reporter Genes; Research Personnel; Resistance; Resources; Response Elements; Rheumatoid Arthritis; Screening procedure; Signal Transduction; Species Specificity; Therapeutic; Therapeutic Agents; Toxic effect; Translating; Vaccine Adjuvant; Vaccines; Viral; Viral Proteins; Viral Vaccines; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; Work; base; design; drug resistant virus; high throughput screening; human disease; innovation; leukemia; novel; novel virus; pathogen; pre-clinical; prevent; promoter; red fluorescent protein; resistant strain; response; small molecule; virology

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.

描述（由申请人提供）：先天免疫反应代表了抵御病毒感染的第一道屏障，并提供了形成适当免疫反应所需的初始信号。干扰素 (IFN) 是先天免疫系统的关键要素，是目前有效对抗多种病毒感染的治疗剂。然而，对于没有疫苗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阻止病毒复制的细胞抗病毒状态，因此诱导和/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。 该应用旨在鉴定干扰素诱导小分子化合物，用于治疗广谱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具有直接而重大的影响。我们将使用一种新颖、简单且灵敏的基于细胞的测定来识别诱导和/或激活先天免疫反应的化合物。 为了实现这一目标，我们将：开发并采用基于细胞的测定法来识别诱导和/或激活先天免疫反应的化合物（目标 1）。具体来说，我们将筛选两个结构不同的小分子化合物库，以证明我们的基于细胞的测定法转化为自动化高通量筛选（HTS）格式的可行性。接下来，我们将使用二次测定来验证已识别的命中及其生物学相关性（目标 2）。我们将证明在初级筛选中具有活性的化合物通过二次测定为阳性命中，评估其物种特异性、作用机制和毒性，以便优先考虑它们在抗病毒测定中的表征。 我们简单的基于细胞的测定代表了一种全面而可靠的方法，可立即鉴定有前途的 IFN 调节剂，以治疗依赖于 IFN 独特用途的病毒感染和其他人类疾病。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化合物的抗病毒特性，以选择主要候选治疗药物。 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 (IFN) 反应会在细胞中诱导抗病毒状态，从而阻止病毒复制，因此增强或激活 IFN 反应的化合物代表了作为抗病毒药物、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检测，我们将鉴定干扰素调节化合物，这些化合物将成为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。