Norovirus Capsid: a Novel Drug Target

诺如病毒衣壳：新型药物靶点

• 批准号: 8713910
• 负责人: JAREK MELLER
• 金额: $ 19.45万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-06 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713910
• 关键词: Acute; Address; Affect; Allosteric Site; Antiviral Agents; Arts; Base Sequence; Benchmarking; Binding; Biological Assay; Biological Models; Calicivirus; Capsid; Capsid Proteins; Complement; Consensus; Data; Development; Disease Outbreaks; Docking; Drug Targeting; Electron Microscopy; Epidemic; Figs - dietary; Future; Gastroenteritis; Gel Chromatography; Goals; HIV; Hepatitis B Virus; Hot Spot; Human; Human poliovirus; In Vitro; Infection; Lead; Libraries; Maps; Methods; Modeling; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Mutagenesis; Mutation; Norovirus; Pharmaceutical Preparations; Polioviruses; Proteins; Public Health; Site; Slide; Structural Protein; Structure; Structure-Activity Relationship; Testing; Therapeutic; Vaccines; Validation; Viral; Virus; Virus Diseases; base; candidate identification; candidate validation; cheminformatics; computer framework; computer studies; flexibility; in vivo; inhibitor/antagonist; mortality; novel; novel strategies; novel therapeutic intervention; particle; prophylactic; public health relevance; research study; screening; simulation; small molecule; stem; therapeutic target; tool; virtual

DESCRIPTION (provided by applicant): Noroviruses (NVs) are the most important cause of non-bacterial epidemics of acute gastroenteritis, which is a common cause of morbidity and mortality worldwide. In US, outbreaks of NV-related gastroenteritis are estimated to affect 23 million people annually, representing a significant threat to public health. With the goal of developing novel therapeutic approaches for the treatment of NV infection, this proposal aims to identify small molecules that can effectively destabilize and/or disrupt the assembly of the NV capsid. Targeting NV capsid represents a novel strategy that has been successfully applied to other viruses in recent years. The proposed approach stems from our previous collaborative efforts and builds on expertise in both NV research and computational studies of proteins and their interactions. We propose an integrated strategy that uniquely combines: i) a novel computational framework for modeling and ranking of hot spots within NV capsid proteins; ii) virtual screening for small molecules targeting such sites; iii) experimental validation of top hit using newly established functional and structural assays and different model systems. Mapping of functional and structural hot spots will utilize the wealth of sequence and structural data on NVs. Ranking and assessment of the predicted hot spots will be further enhanced by integrating evolutionary, structural and functional information with modeling of conformational changes and allosteric effects associated with oligomerization of capsid proteins. Validation and further characterization of such identified hot spots will be performed by using mutagenesis, in vitro binding and in vivo functional assays. Virtual screening using state-of-art docking simulations, cheminformatic methods and comprehensive libraries of drug-like compounds will be used to identify candidate molecules targeting top ranking sites. Experimental validation of top hits will be performed using in vitro binding and in vivo functional assays developed by us recently for the assessment of NV capsid assembly. In order to facilitate this and future applications to other viruses, a versatile interface for automated analysis of structural and functional hot spots within capsid proteins will be integrated into our Polyview-MM portal.

描述（由申请人提供）：诺如病毒（NVs）是急性胃肠炎非细菌性流行的最重要原因，是世界范围内发病率和死亡率的常见原因。在美国，估计每年有2300万人爆发与新冠病毒有关的肠胃炎，对公共卫生构成重大威胁。为了开发治疗NV感染的新治疗方法，本提案旨在识别能够有效破坏和/或破坏NV衣壳组装的小分子。靶向NV衣壳是近年来成功应用于其他病毒的一种新策略。提出的方法源于我们以前的合作努力，并建立在NV研究和蛋白质及其相互作用的计算研究的专业知识之上。我们提出了一个独特的综合策略：i)一个新的计算框架，用于NV衣壳蛋白内热点的建模和排序；Ii)针对这些位点的小分子虚拟筛选；Iii)利用新建立的功能和结构分析以及不同的模型系统对顶击进行实验验证。功能和结构热点的映射将利用NVs丰富的序列和结构数据。将进化、结构和功能信息与衣壳蛋白寡聚化相关的构象变化和变构效应建模相结合，进一步加强对预测热点的排序和评估。将通过诱变、体外结合和体内功能分析来验证和进一步表征这些已确定的热点。虚拟筛选使用最先进的对接模拟，化学信息学方法和药物样化合物的综合文库将用于识别靶向顶级位点的候选分子。实验验证将使用体外结合和体内功能分析来进行，这是我们最近开发的用于评估NV衣壳组装的方法。为了方便这和未来的其他病毒的应用，一个多功能的接口，用于自动分析结构和功能热点