Pathogenesis & Antivirals for Noroviruses

发病

• 批准号: 10674957
• 负责人: Robert L. Atmar
• 金额: $ 45.01万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674957
• 关键词: Acute; Address; Affinity; Alanine; Antibodies; Antibody Repertoire; Antigens; Antiviral Agents; Bile Acids; Binding; Biological Assay; Blocking Antibodies; Blood Group Antigens; Cell Death; Cells; Clinical; Clinical Data; Coculture Techniques; Collaborations; Complement; Development; Disease; Drug Design; Enteroendocrine Cell; Epithelial Cells; Epitope Mapping; Epitopes; Evaluation; Feces; Gastroenteritis; Gastrointestinal tract structure; Gene Expression Profile; Goals; Grant; Hormones; Human; Immobilization; Immune; Immune response; Immune system; Immunity; In Vitro; Individual; Infection; Intestines; Libraries; Maps; Mediating; Mediator; Metabolic; Modeling; Molecular Conformation; Monoclonal Antibodies; Morphology; Mutagenesis; Norovirus; Norwalk virus; Open Reading Frames; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peptide Phage Display Library; Peptides; Phage Display; Pharmaceutical Chemistry; Pharmaceutical Preparations; Polymerase; Preclinical Testing; Production; Proteins; Public Health; Sampling; Scanning; Serotonin; Serum; Severities; Site; Symptoms; System; Testing; Therapeutic; Tight Junctions; Time; United States; Vaccine Design; Vaccines; Viral; Viral Load result; Viral Pathogenesis; Viral Physiology; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; Virus-like particle; Work; X-Ray Crystallography; antigen binding; antiviral drug development; cell type; clinically relevant; cross reactivity; cytokine; deep sequencing; design; drug candidate; drug testing; experimental study; human data; improved; in vivo; inhibitor; insight; intestinal epithelium; multiplex assay; neutralizing antibody; novel strategies; pathogen; peptidomimetics; preclinical development; prevent; response; screening; small molecule inhibitor; vaccine development; vaccine evaluation

PROJECT SUMMARY Human noroviruses (HuNoVs) are a leading causes of gastroenteritis in the United States and globally. The significant public health burden associated with this pathogen has stimulated efforts in vaccine development and in the evaluation of antivirals. However, a number of fundamentally important questions on virus pathogenesis and protective immune responses remain unanswered and addressing these challenges is critical for the development of effective strategies to prevent and treat HuNoV infections. In this project, we aim to: (i) Elucidate factors that mediate clinical presentations associated with HuNoV gastroenteritis; (ii) Develop and pre-clinically test drug-like inhibitors of virus protease and polymerase as potential antiviral agents; and (iii) Determine HuNoV epitopes recognized by the human immune system during infection and identify epitopes associated with virus neutralization and protective immunity. Using clinical data and samples from previous human experimental challenge studies, together with infectivity assays in human intestinal enteroids (HIEs) allows us to carry out functional and mechanistic on HuNoV pathogenesis and virus neutralization. The HIE cultivation system also, for the first time, allows us to directly evaluate antivirals. The findings from this project will therefore provide new understanding of the mechanisms of HuNoV disease and identify potential targets that can used to treat disease symptoms. Drug-like inhibitors prioritized through rational drug design and medicinal chemistry will be evaluated for their effects on inhibition of virus and key factors associated with infection and disease. Finally, identification of antibody repertoires that correlate with protective immunity and virus neutralization will inform vaccine design and testing. Together, these studies will enable functional, mechanistic and translational contributions that will reduce the public health burden of HuNoV gastroenteritis. .

项目概要 人类诺如病毒 (HuNoV) 是美国和全球胃肠炎的主要原因。这 与这种病原体相关的重大公共卫生负担刺激了疫苗开发和 在抗病毒药物的评价中。然而，关于病毒发病机制的一些根本性重要问题 保护性免疫反应仍未得到解决，解决这些挑战对于 制定预防和治疗 HuNoV 感染的有效策略。 在这个项目中，我们的目标是： (i) 阐明介导 HuNoV 相关临床表现的因素 胃肠炎; (ii) 开发并进行临床前测试病毒蛋白酶和聚合酶的药物样抑制剂 潜在的抗病毒药物； (iii) 确定人类免疫系统在感染期间识别的 HuNoV 表位 感染并识别与病毒中和和保护性免疫相关的表位。 使用先前人体实验挑战研究的临床数据和样本以及传染性 人类肠类肠 (HIE) 检测使我们能够对 HuNoV 进行功能和机制研究 发病机制和病毒中和。 HIE 培养系统还首次允许我们直接 评估抗病毒药物。因此，该项目的研究结果将为该机制提供新的理解 HuNoV 疾病并确定可用于治疗疾病症状的潜在靶点。类药物抑制剂 通过合理的药物设计和药物化学优先考虑它们对抑制的影响 病毒以及与感染和疾病相关的关键因素。最后，鉴定抗体库 与保护性免疫和病毒中和相关的信息将为疫苗设计和测试提供信息。在一起，这些 研究将实现功能性、机械性和转化性贡献，从而减轻公共卫生负担 HuNoV 胃肠炎。 。