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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：
8297725
负责人：
Mark E. Peeples
金额：
$ 12.07万
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 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8297725
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 Delivery Systems 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. PUBLIC HEALTH RELEVANCE: Respiratory syncytial virus is the most important respiratory pathogen for infants, and second only to influenza virus for the elderly. Infection begins with fusion of the virus membrane with the cell membrane, driven by the viral F glycoprotein. It undergoes massive changes in shape to accomplish this. We have developed a model of the F protein and used it to predict functional domains, and a soluble version of the F protein to test these predictions, enabling future development of targeted antiviral drugs and a novel vaccine.

描述（由申请人提供）：呼吸道合胞病毒（RSV）感染仍然是婴儿和老年人的重要医学问题。感染需要病毒膜与靶细胞膜融合，从而将病毒基因组传递到靶细胞质中。病毒融合蛋白(F)，三种RSV糖蛋白之一，执行这一作用。它