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Conformational change in HSV glycoprotein B

HSV糖蛋白B的构象变化

基本信息

批准号：
8501355
负责人：
ANTHONY V NICOLA
金额：
$ 17.74万
依托单位：
WASHINGTON STATE UNIVERSITY
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：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501355
关键词：
Antiviral Agents Automobile Driving Binding Biochemical Biochemistry Biological Assay Blindness Cell fusion Cell membrane Cells Cellular biology Complex Cytoplasmic Tail Data Development Disease Doctor of Philosophy Drug resistance Encephalitis Endocytosis Endocytosis Pathway Epithelial Cells Experimental Designs Glycoproteins Goals Herpes Labialis Herpesviridae Human Hydrophobicity In Vitro Infection Intervention Knowledge Lead Length Measures Mediating Membrane Fusion Modeling Molecular Molecular Conformation Molecular Virology Morbidity - disease rate Neonatal Newborn Infant Peptides Play Process Proteins Reaction Regulation Research Role Shapes Simplexvirus Staging Structure System Techniques Testing Viral Virus Virus Diseases Virus-Cell Membrane Interaction Work base cell type defined contribution genital infection glycoprotein structure inhibitor/antagonist latent infection mortality mutant novel pathogen prevent receptor virus envelope

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) causes lifelong latent infections in humans. It is responsible for significant disease, ranging from cold sores and genital infections to neonatal infections, blindness and fatal encephalitis. The long-term goal of this project is to understand the molecular mechanisms that HSV uses to gain entry into host cells. Herpesvirus membrane fusion and entry is a complex cascade of interactions involving multiple viral glycoproteins and multiple cellular triggers. An emerging concept in herpesvirology is that the endosomal pH of the host cell is required for viral entry, often in a cell type specifi manner. The mechanistic role that low pH plays is not clear. We recently identified HSV envelope glycoprotein B (gB) as the principal target of endosomal pH. Mildly acidic pH reversibly alters the antigenic structure and oligomeric conformation of gB in vitro and during virus entry into cells. Based on these newly identified conformational changes, we propose to develop herpesviral entry inhibitors and to elucidate the role of gB in driving the fusion reaction In Specific Aim # 1, we will test the hypothesis that gB conformation change is a novel target for antiviral intervention. We will identify specific and potent peptide inhibitors of gB structural transition. Inhibitors will be assessed for the ability to block viral membrane fusion and entry. I Specific Aim # 2, we will define the contribution of the gB cytoplasmic tail to its conformation change and membrane fusion. Our experimental design employs techniques of cell biology, biochemistry, and molecular virology. HSV utilizes a pH-dependent endocytosis pathway in epithelial cells, the initial portal of entry in the human host. Thus, achieving these aims will delineate a key step in the mechanism of the initial infection of target cells and reveal a means to prevent it. The results will provide a mechanistic understanding of conformational change in gB and its relation to membrane fusion.

描述(申请人提供)：单纯疱疹病毒(HSV)会导致人类终身潜伏感染。它是重大疾病的罪魁祸首，从唇疱疹和生殖器感染到新生儿感染、失明和致命的脑炎。该项目的长期目标是了解单纯疱疹病毒进入宿主细胞的分子机制。疱疹病毒膜融合和进入是一个复杂的级联反应，涉及多种病毒糖蛋白和多种细胞触发因子。疱疹病毒学中的一个新概念是，宿主细胞的内体pH是病毒进入所需的，通常是以细胞类型特有的方式。低pH值所起的作用机制尚不清楚。我们最近发现单纯疱疹病毒包膜糖蛋白B(GB)是影响内膜pH的主要靶点。在体外和病毒进入细胞过程中，温和的酸性pH可逆地改变gB的抗原结构和寡聚体构象。基于这些新发现的构象变化，我们建议开发疱疹病毒进入抑制剂，并在特定的目标1中阐明Gb在推动融合反应中的作用，我们将检验Gb构象变化是抗病毒干预的新靶点的假设。我们将确定特异性的和有效的GB结构转换的多肽抑制剂。将评估抑制剂阻止病毒膜融合和进入的能力。在具体目标2中，我们将确定GB细胞质尾巴在其构象变化和膜融合中的作用。我们的实验设计采用了细胞生物学、生物化学和分子病毒学技术。HSV在上皮细胞中利用一种依赖于pH的内吞途径，这是进入人类宿主的初始入口。因此，实现这些目标将勾勒出靶细胞初始感染机制的关键一步，并揭示预防它的方法。这些结果将从机理上理解GB的构象变化及其与膜融合的关系。