Norovirus Capsid: a Novel Drug Target

诺如病毒衣壳：新型药物靶点

基本信息

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
项目类别：
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

项目摘要

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）：北病毒（NVS）是急性胃肠炎的非细菌流行病的最重要原因，这是全球发病率和死亡率的常见原因。在美国，据估计，与NV相关的胃肠炎爆发估计每年会影响2300万人，这对公共卫生构成了重大威胁。为了开发新的治疗方法来治疗NV感染，该建议旨在确定可以有效地破坏和/或破坏NV Capsid组装的小分子。靶向NV CapSID代表了一种新型策略，近年来已成功应用于其他病毒。所提出的方法源于我们以前的合作努力，并以NV研究和蛋白质及其相互作用的计算研究的专业知识为基础。我们提出了一种唯一结合的集成策略：i）一种新型的计算框架，用于建模和排名NV Capsid蛋白质中的热点； ii）针对此类位点的小分子的虚拟筛选； iii）使用新建立的功能和结构测定以及不同模型系统对最高命中的实验验证。功能和结构热点的映射将利用NVS上的大量序列和结构数据。通过将进化，结构和功能信息与构象变化的建模和与帽壳蛋白的寡聚相关的构象变化和变构效应的建模，将进一步增强对预测热点的排名和评估。通过使用诱变，体外结合和体内功能测定，将对这种鉴定的热点进行验证和进一步表征。使用最先进的对接模拟，化学物质方法和类似药物样化合物的全面库进行虚拟筛查，用于识别针对排名最高点的候选分子。最高命中的实验验证将使用美国最近为评估NV CAPSID组装而开发的体外结合和体内功能测定。为了促进对其他病毒的这种应用和将来的应用，这是一种用于自动分析结构和功能热点的多功能接口衣壳蛋白将集成到我们的PolyView-MM门户中。