Pathogenesis and Antivirals for Noroviruses

诺如病毒的发病机制和抗病毒药物

• 批准号: 9292240
• 负责人: Robert L. Atmar
• 金额: $ 36.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9292240
• 关键词: Acute; Adult; Affinity; Age; Antibodies; Antibody Diversity; Antibody Repertoire; Antibody Response; Antigenic Variation; Antigens; Antiviral Agents; Antiviral Therapy; Binding; Biological; Biological Assay; Blocking Antibodies; Capsid Proteins; Centers for Disease Control and Prevention (U.S.); Child; Chronic; Cloning; Collaborations; Development; Disease Outbreaks; Dissection; Drug Design; Drug Kinetics; Elderly; Epidemic; Evaluation; Exposure to; Frequencies; Funding; Gastroenteritis; Generations; Genetic; Genetic Transcription; Genetic Variation; Genotype; Goals; High-Throughput Nucleotide Sequencing; Human; Humoral Immunities; Illness Days; Immune response; Immunocompetent; Immunocompromised Host; Immunoglobulins; In Vitro; Individual; Infection; Light; Location; Long-Term Care; Measures; Medicine; Metabolic; Methods; Molecular; Monoclonal Antibodies; Mutation; Norovirus; Pathogenesis; Peptide Hydrolases; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasmablast; Polysaccharides; Population; Populations at Risk; Prevention; Prevention strategy; Property; Prophylactic treatment; RNA replication; Reagent; Reporting; Research; Risk; Sampling; Serum; Source; Specificity; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Therapeutic Uses; Time; Toxicology; United States; Variant; Viral; Viral reservoir; Virus; Virus Shedding; age group; antigen binding; base; design; drug candidate; economic impact; health economics; high throughput screening; human monoclonal antibodies; immunological status; improved; inhibitor/antagonist; mimetics; molecular diagnostics; particle; preclinical trial; prevent; prophylactic; response; small molecule inhibitor; treatment strategy; vaccine development; viral RNA; virus genetics; young adult

PROJECT SUMMARY: Project 1 The focus of Project 1 is to increase our understanding of the pathogenesis of norovirus infection and to develop treatment and prevention strategies that can be applied to infected and at risk populations. Human noroviruses are the most common cause of epidemic and sporadic gastroenteritis in the United States, causing both significant health and economic impact, but we currently have only non-specific measures to prevent and treat infection. Our prior research has shown that persons with serum antibody that blocks binding of viral particles to putative glycan attachment factors have decreased risks of illness and infection after exposure to virus, and that following infection such blocking antibodies can develop against heterologous strains. Nevertheless, a major potential barrier to vaccine development is the significant genetic and antigenic variation that occurs. Chronic infection among immunocompromised patients has been proposed as one source of emergent variants. We hypothesize that infections in children and elderly individuals are another source of viral variants. In Specific Aim 1 we will determine whether the frequency of emergent variants is greater in children or the elderly compared to immunocompetent adults, and the frequency of these variants will be contrasted with that observed in an immunocompromised population. The potential impact of genetic changes on VP1 structures (e.g., in histoblood group antigen binding specificities) will be assessed in collaboration with Project 3. Viral strains collected in this project will also be used in cultivation studies in Project 2. In Specific Aim 2, we will perform studies to better understand the humoral immune response induced following infection. We will test the hypothesis that the generation of antibody responses to genotypes distinct from the infecting strain is more common in immunocompetent adults than in children. Human monoclonal antibodies will be made by cloning the heavy and light chain variable domains from plasmablasts generated during acute infection, and expressing these in combination with immunoglobulin constant domains. Antibody reactivity and the ability of the antibodies to block virus-glycan interactions against homotypic and heterotypic strains will be determined. Antibodies that block virus-glycan interactions for a large number of genotypes may have value for use in prophylaxis of risk groups. In Specific Aim 3, we will use an integrated strategy including structure-based inhibitor design, synthetic medicinal chemistry, structure activity relationship analysis, and toxicological studies to develop and characterize antivirals targeting the viral protease. Structural information about key inhibitors developed in this aim will be obtained in collaboration with Project 3. Monoclonal antibodies and antiviral agents developed in Aims 2 and 3 will be evaluated for activity in RNA expression and replication systems developed in Project 2. Overall, these studies are designed to understand and evaluate the importance of age and immune status on virus variation and on the development of potential humoral immunity and to develop reagents that can be used to prevent or treat norovirus infection.

项目概要：项目 1 项目1的重点是增加我们对诺如病毒感染发病机制的了解，并 制定可适用于感染者和高危人群的治疗和预防策略。人类 诺如病毒是美国流行性和散发性胃肠炎的最常见原因， 造成重大的健康和经济影响，但我们目前只有非具体措施 预防和治疗感染。我们之前的研究表明，血清抗体阻断的人 病毒颗粒与假定的聚糖附着因子的结合降低了疾病和感染的风险 接触病毒后，感染后可以产生针对异源的阻断抗体 菌株。然而，疫苗开发的一个主要潜在障碍是显着的遗传和抗原性 发生的变异。免疫功能低下患者的慢性感染已被提议作为一种 紧急变体的来源。我们假设儿童和老年人的感染是另一个原因 病毒变种的来源。在具体目标 1 中，我们将确定紧急变体的频率是否为 与免疫功能正常的成年人相比，儿童或老年人的变异更大，以及这些变异的频率 将与免疫功能低下人群中观察到的情况形成对比。遗传的潜在影响 VP1 结构的变化（例如，组织血型抗原结合特异性）将在 与项目3合作。该项目中收集的病毒株也将用于栽培研究 项目 2. 在具体目标 2 中，我们将进行研究以更好地了解体液免疫反应 感染后诱发。我们将检验以下假设：抗体反应的产生 与感染株不同的基因型在免疫功能正常的成人中比在儿童中更常见。 人单克隆抗体将通过克隆重链和轻链可变域来制备 急性感染期间产生的浆母细胞，并与免疫球蛋白结合表达它们 恒定域。抗体反应性和抗体阻断病毒-聚糖相互作用的能力 将确定针对同型和异型菌株的效果。阻止病毒-聚糖相互作用的抗体 对于大量基因型来说，可能具有用于危险人群预防的价值。在具体目标 3 中，我们 将采用综合策略，包括基于结构的抑制剂设计、合成药物化学、 结构活性关系分析和毒理学研究，以开发和表征抗病毒药物 靶向病毒蛋白酶。将获得有关为此目的开发的关键抑制剂的结构信息 与项目 3 合作。目标 2 和 3 中开发的单克隆抗体和抗病毒药物将 评估项目 2 中开发的 RNA 表达和复制系统的活性。总体而言，这些 研究旨在了解和评估年龄和免疫状态对病毒变异的重要性 以及潜在体液免疫的发展，并开发可用于预防或预防的试剂 治疗诺如病毒感染。