Understanding fusion peptide mutations in influenza hemagglutinin

了解流感血凝素的融合肽突变

• 批准号: 8294116
• 负责人: Peter M Kasson
• 金额: $ 28.46万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294116
• 关键词: Affect; Antiviral Agents; Antiviral Therapy; Biological Assay; Biological Models; Capsid Proteins; Cell membrane; Cells; Cessation of life; Chimeric Proteins; Coupled; Data; Defect; Development; Elements; Environment; Experimental Models; Goals; Hemagglutinin; Human; Infection; Influenza; Influenza Hemagglutinin; Knowledge; Laboratories; Length; Life; Lipids; Membrane; Membrane Fusion; Membrane Lipids; Methods; Modeling; Modification; Mutagenesis; Mutation; Nature; Outcome; Pathway interactions; Peptides; Performance; Pharmaceutical Preparations; Phenotype; Point Mutation; Process; Proteins; Sterols; Structural Models; Structure; Study models; Testing; Therapeutic Agents; United States; Vesicle; Viral; Virion; Virus; Work; base; influenzavirus; membrane assembly; molecular scale; mutant; novel therapeutics; pathogen; simulation; theories; therapy development

DESCRIPTION (provided by applicant): Influenza is both a major human pathogen, causing approximately 50,000 deaths per year in the United States and a well-studied model system for cell entry by enveloped viruses. Influenza enters cells via a process of membrane fusion, but despite extensive study the mechanism by which influenza hemagglutinin catalyzes this process is not well understood. Experimental mutagenesis has yielded much data on the functional requirements of influenza fusion proteins, but we have no robust theory that could have predicted these results. This proposal seeks to develop a robust understanding of fusion peptide mechanisms sufficient to predict such mutations to hemagglutinin. We also wish to establish which elements of influenza entry are common to all membrane fusion, as modifications to the lipid environment can also promote or block fusion, and which may be virus-specific. We are developing high-performance simulation methods to analyze membrane fusion; in this work, we will use these methods to predict how mutations to influenza fusion peptides alter the virus's ability to infect cells and to investigate how lipid composition changes interact with these mutations to control viral infectivity. Computational predictions will be evaluated against experimental assays performed in the laboratory of collaborator Steinhauer. PUBLIC HEALTH RELEVANCE: This project studies how influenza coat proteins interact with cell membranes to infect the cell. By studying how viral mutations can interfere with this process, we hope to uncover new strategies for antiviral treatment.

描述（由申请人提供）：流感既是人类的主要病原体，在美国每年大约50,000例死亡，也是被包膜病毒细胞进入细胞的良好模型系统。流感通过膜融合过程进入细胞，但是尽管进行了广泛的研究，但流感脑血凝集素催化这一过程的机制尚不清楚。实验诱变已经产生了有关流感融合蛋白功能需求的大量数据，但是我们没有可预测这些结果的强大理论。该提案旨在对融合肽机制进行强有力的理解，以预测到血凝集素的这种突变。我们还希望确定所有膜融合的流感输入元素都是共同的，因为对脂质环境的修改也可以促进或阻止融合，并且可能是特定于病毒的。我们正在开发高性能模拟方法来分析膜融合。在这项工作中，我们将使用这些方法来预测流感融合肽的突变如何改变病毒感染细胞的能力，并研究脂质组成变化如何与这些突变相互作用以控制病毒感染性。计算预测将根据合作者Steinhauer实验室进行的实验测定进行评估。 公共卫生相关性：该项目研究了流感外壳蛋白如何与细胞膜相互作用以感染细胞。通过研究病毒突变如何干扰这一过程，我们希望发现新的抗病毒药物治疗策略。