Spike protein cleavage-activation and emergence of coronaviruses with extended tr

刺突蛋白裂解激活和延长时间的冠状病毒的出现

• 批准号: 8682461
• 负责人: Gary R Whittaker
• 金额: $ 19.13万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682461
• 关键词: Antiviral Agents; Attention; Bioinformatics; Cell membrane; Cells; Communicable Diseases; Communities; Coronavirus; Data; Development; Disease Outbreaks; Genome; Goals; Health Planning; Homologous Gene; Human; Infection; Lead; Life Cycle Stages; Mediating; Membrane Fusion; Middle East; Modeling; Modification; Mutation; Names; Nature; Pathway interactions; Peptide Hydrolases; Positioning Attribute; Process; Proteins; Proteolysis; Public Health; Relative (related person); Role; Site; Syndrome; Testing; Therapeutic; Tissues; Tropism; Viral; Viral Fusion Proteins; Viral Pathogenesis; Virion; Virus; Work; base; cell type; human coronavirus; in vivo; inhibitor/antagonist; interest; mutant; novel; paired basic amino acid cleaving enzyme; public health relevance; respiratory

DESCRIPTION (provided by applicant): Recently, coronaviruses have generated substantial interest from the biomedical community based on the emergence and isolation of a novel and deadly coronavirus infecting humans. This virus was recently named Middle East Respiratory Syndrome (MERS)-CoV. Like other enveloped viruses, coronaviruses access their host cells by membrane fusion, a process mediated by a specific fusion, or "spike" protein on the virion. Such viral fusion proteins are often activated by host cell proteases. Mutations in the virus genome can lead to modifications to the proteolytic cleavage sites(s) on the spike that can subsequently regulate membrane fusion, virus entry and host cell tropism. We have identified changes in the MERS-CoV spike protein cleavage site(s) that distinguish it from its closest relatives, as well as most other coronaviruses. These changes allow cleavage-activation of the spike protein by furin, a broadly expressed protease. Furin-mediated activation is unusual in that it occurs during virus entry. The ability of MERS-CoV to utilize furin in this manner may explain the polytropic nature of the virus and its life cycle as a zoonotic coronavirus. In this application, we will characterize the proteolytic cleavage sites of MERS-CoV spike, in comparison to its closest relatives BatCoV- HKU4 and BatCoV-HKU5, and determine the role of furin-mediated cleavage in the context of the polytropic nature of MERS-CoV. More broadly, our goals are to understand how mutations in the CoV spike cleavage sites modulate protease cleavage and fusion activation. Our work will be useful for public health planning and in testing the feasibility of usng furin inhibitors as anti-viral therapeutics for MERS-like CoV infections.

描述（由申请人提供）：最近，基于感染人类的新型致命冠状病毒的出现和分离，冠状病毒引起了生物医学界的极大兴趣。这种病毒最近被命名为中东呼吸综合征（MERS）-CoV。与其他包膜病毒一样，冠状病毒通过膜融合进入宿主细胞，这是一个由病毒粒子上的特定融合或“刺突”蛋白介导的过程。这种病毒融合蛋白通常被宿主细胞蛋白酶激活。病毒基因组中的突变可导致刺突上的蛋白水解切割位点的修饰，其随后可调节膜融合、病毒进入和宿主细胞嗜性。我们已经确定了MERS-CoV刺突蛋白切割位点的变化，这些变化将其与其最近的亲戚以及大多数其他冠状病毒区分开来。这些变化允许弗林蛋白酶（一种广泛表达的蛋白酶）切割激活刺突蛋白。弗林蛋白酶介导的激活是不寻常的，因为它发生在病毒进入。MERS-CoV以这种方式利用弗林蛋白酶的能力可以解释病毒的多变性及其作为人畜共患冠状病毒的生命周期。在本申请中，我们将表征MERS-CoV刺突的蛋白水解切割位点，与其最接近的亲戚BatCoV-HKU 4和BatCoV-HKU 5相比，并确定弗林蛋白酶介导的切割在MERS-CoV的多变性背景下的作用。更广泛地说，我们的目标是了解冠状病毒刺突切割位点的突变如何调节蛋白酶切割和融合激活。我们的工作将有助于公共卫生规划和测试使用弗林蛋白酶抑制剂作为MERS样CoV感染的抗病毒疗法的可行性。