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Mechanism of Respiratory Syncytial Virus Fusion

呼吸道合胞病毒融合机制

基本信息

批准号：
9001238
负责人：
Mark E. Peeples
金额：
$ 36.2万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9001238
关键词：
Admission activity Alanine Amino Acids Antiviral Agents Apical Back Binding Buffers Cell fusion Cell membrane Cell surface Cell-Matrix Junction Cells Cessation of life Cleaved cell Computer Simulation Cytoplasm Developed Countries Development Drug Targeting Elderly Event Future Glycoproteins Goals Infant Infection Intervention Ion Channel Laboratories Lead Matched Group Medical Membrane Membrane Fusion Modeling Movement Mutagenesis Mutation N-terminal Palivizumab Paramyxovirus Pediatric Hospitals Peptides Pharmaceutical Preparations Physiological Play Positioning Attribute Potential Energy Process Proteins Reporting Respiratory Syncytial Virus Infections Respiratory syncytial virus Respiratory syncytial virus RSV F proteins Risk Role Safety Shapes Site Stimulus Structure System Testing Time Vaccines Viral Viral Genome Virion Virus Virus Diseases base cellular targeting drug development end of life glycoprotein G health care delivery high throughput screening humanized monoclonal antibodies influenzavirus novel novel vaccines pathogen prevent protein function respiratory small molecule small molecule libraries vaccine development

项目摘要

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) infection remains an important medical problem for infants and the elderly. Infection requires the fusion of the vira membrane with the target cell membrane, which delivers the viral genome into the target cell cytoplasm. The viral fusion (F) protein, one of the three RSV glycoproteins, performs this role. It is clear from the crystal structures of two related viruses, one in the pre-triggered and one in th post-triggered form, that the F protein undergoes massive changes in structure to accomplish membrane fusion. Based on these structures, models of the pre-triggered and post-triggered RSV F protein have been generated. Using the pre-triggered model, the most likely sites for attachment to target cells and/or for triggering have been identified. Mutation of the amino acids in these sites to alanine will test their importance in cell-cell fusion. Mutations that prevent fuion without preventing the F protein from reaching the cell surface will be studied biochemically for their attachment and triggering abilities. For these studies, a soluble (sF) version of the F proten in its pre-triggered form has been produced for the first time, and shown to be triggered by a reduction in molarity. The possibility that reduced molarity causes F protein triggering will also be investigated since its mechanism may provide novel antiviral drug targets. Overall, these studies will result in the identification of functional domains in the F protein that can be used t rapidly screen for novel antiviral compounds and to develop novel vaccines.

描述（由申请人提供）：呼吸道合胞病毒（RSV）感染对于婴儿和老年人来说仍然是一个重要的医疗问题。感染需要病毒膜与靶细胞膜融合，从而将病毒基因组递送到靶细胞的细胞质中。病毒融合 (F) 蛋白（RSV 三种糖蛋白之一）发挥着这一作用。它从两种相关病毒（一种处于触发前形式，一种处于触发后形式）的晶体结构中可以清楚地看出，F 蛋白在结构上经历了巨大的变化以实现膜融合。基于这些结构，已经生成了触发前和触发后 RSV F 蛋白的模型。使用预触发模型，已经确定了最有可能附着到靶细胞和/或触发的位点。这些位点的氨基酸突变为丙氨酸将测试它们在细胞-细胞融合中的重要性。阻止融合而不阻止 F 蛋白到达细胞表面的突变将通过生化方法研究其附着和触发能力。在这些研究中，首次生产了预触发形式的 F 蛋白的可溶性 (sF) 版本，并证明是通过摩尔浓度的降低来触发的。摩尔浓度降低导致 F 蛋白触发的可能性也将得到研究，因为其机制可能提供新的抗病毒药物靶点。总体而言，这些研究将鉴定 F 蛋白中的功能域，可用于快速筛选新型抗病毒化合物并开发新型疫苗。