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针对病毒感染的第一个障碍，并提供了开发适当的免疫反应所需的初始信号。干扰素（IFN）构成了先天免疫系统的关键元素，并且是当前的治疗剂，可有效地针对广泛的病毒感染。然而，对于高致病性病毒或对病毒抑制剂抗性病毒菌株的高度致病性病毒，特别需要新的抗病毒药。因为IFN反应诱导了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表示令人兴奋的候选者作为治疗病毒感染的治疗剂。 该应用旨在鉴定诱导干扰素的小分子化合物，以治疗广泛的病毒感染和其他与干扰素相关的人类疾病。这些诱导的干扰素诱导化合物也可以用作病毒疫苗的免疫调节剂和/或佐剂，这说明了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测定方法来识别诱导和/或激活先天免疫反应的化合物。 为了实现这一目标，我们将：开发和调整基于细胞的测定法，以识别诱导和/或激活先天免疫反应的化合物（AIM 1）。具体而言，我们将筛选两个结构上多样的小分子化合物的文库，以证明我们的基于细胞的测定法的可行性，该测定法被转化为自动化的高通量筛选（HTS）格式。接下来，我们将使用次要测定来验证已识别的命中及其生物学相关性（AIM 2）。我们将通过次要测定来证明主筛选中活跃的化合物为正命中，评估它们的物种特异性，作用机理和毒性机制，以便优先考虑其在抗病毒测定中的表征。 我们的直接基于细胞的分析代表了立即鉴定有希望的IFN调节剂治疗病毒感染和其他依赖IFN独特使用的人类疾病的全面和可靠的方法。该项目将使我们能够实现临床前动物模型中确定化合物的抗病毒特性的长期目标，以选择铅治疗候选。 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度致病性病毒或对病毒抑制剂具有抗性的病毒菌株。因为干扰素（IFN）反应在细胞中诱导了防止病毒复制的抗病毒态，因此增强或激活IFN反应的化合物代表了铅候选者作为抗病毒药，疫苗佐剂或潜在的免疫调节剂。使用我们的高吞吐量基于细胞的测定，我们将确定将代表有希望的治疗病毒感染和其他依赖于IFN独特使用的人类疾病的有希望的治疗剂。