Defining the viral PTMome: Towards the development of novel antiviral approaches

定义病毒 PTMome：致力于开发新型抗病毒方法

• 批准号: 10261712
• 负责人: Michaela Ulrike Gack
• 金额: $ 112.7万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10261712
• 关键词: Address; Antiviral Agents; Antiviral Therapy; Biochemical; Cells; Chemicals; Communicable Diseases; Deacetylase; Deubiquitinating Enzyme; Development; Disease; Disease Outbreaks; Enzymes; Future; Gene Targeting; Genetic Techniques; Goals; HIV; Human; Life Cycle Stages; Maps; Molecular; Molecular Virology; Mutate; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Post-Translational Protein Processing; Proteins; Proteome; Proteomics; Public Health; RNA Virus Infections; Regulation; Research; Resistance; Role; Testing; Transferase; Viral; Viral Pathogenesis; Viral Proteins; Virus; Virus Diseases; Virus Replication; biophysical analysis; design; influenzavirus; inhibitor/antagonist; innovation; insight; novel; pandemic disease; pathogenic virus; prevent; reverse genetics; ubiquitin-protein ligase; virology

PROJECT SUMMARY Over the past several decades, the traditional approach to combating viral infectious diseases has been to target the virus itself, in most cases by either blocking virus-encoded enzymes that are required for viral replication, or by preventing the virus from entering host cells. One of the major caveats of these approaches has been the ability of the virus to readily mutate and thereby become resistant to these classical types of antiviral therapies. In fact, this is a serious problem for the therapy of RNA virus infections, such as HIV or influenza virus, which are known to rapidly mutate and thereby escape antiviral drugs. Additionally, traditional antiviral approaches are designed to target a specific virus, and therefore are ineffective against any new virus that may emerge in the future, and it is impossible to predict what virus will cause the next outbreak or pandemic. Therefore, there is the urgent need to develop new ways for targeting viral pathogens, which will require creative and innovative research. Like human proteins, viral proteins robustly undergo posttranslational modifications (PTMs) for their regulation and proper functioning in the virus life cycle. In most cases, viral PTMs are dynamically regulated by human enzymes, such as kinases/phosphatases, ubiquitin E3 ligases/deubiquitinating enzymes, or acetyl transferases/deacetylases. Thus, cellular enzymes play an important role in controlling the ability of the virus to replicate and to cause disease. This proposal’s overarching goal is to comprehensively map the ‘viral PTMome’ to identify the PTMs that are essential for virus replication and pathogenesis. We will combine proteomics screens and molecular virology approaches including reverse genetics techniques with cutting- edge molecular, biochemical and biophysical studies. This will allow us to identify and characterize viral PTMs and the responsible host modifying enzymes, as well as to determine their roles for effective viral replication and pathogenesis. This powerful approach, combined with collaborative studies to design and test chemical inhibitors to block the enzymes that regulate critical viral PTMs, will not only provide unique mechanistic insight into host control of virus replication but will also lay the groundwork for developing new antivirals for a range of emerging viral infectious diseases.

项目摘要 在过去的几十年中，打击病毒感染的传统方法 疾病是针对病毒本身的，在大多数情况下，通过阻断病毒编码 病毒复制所需的酶，或防止病毒进入宿主细胞。 这些方法的主要警告之一是病毒容易突变的能力 从而对这些经典类型的抗病毒疗法有抵抗力。实际上，这是一个 RNA病毒感染治疗的严重问题，例如HIV或影响力病毒， 已知可以快速突变，从而逃脱抗病毒药。另外，传统抗病毒 方法旨在靶向特定病毒，因此对任何新的病毒无效 将来可能出现的病毒，无法预测哪种病毒会导致下一个病毒 爆发或大流行。因此，迫切需要开发靶向病毒的新方法 病原体，这将需要创造性和创新性研究。 像人类蛋白一样，病毒蛋白强烈地进行翻译后修饰 （PTM）在病毒生命周期中调节和适当的功能。在大多数情况下，病毒PTM 由人体酶动态调节，例如激酶/磷酸酶，泛素E3 连接酶/去泛素化酶或乙酰转移/脱乙酰基酶。那就是细胞酶 在控制病毒复制和引起疾病的能力方面发挥着重要作用。 该建议的总体目标是全面绘制“病毒ptmome”以识别 对病毒复制和发病机理必不可少的PTM。我们将结合蛋白质组学 筛选和分子病毒学方法，包括带有切割的反向遗传学技术 边缘分子，生化和生物物理研究。这将使我们能够识别并 特征病毒PTM和负责的宿主修饰酶，并确定 它们在有效的病毒复制和发病机理中的作用。这种强大的方法与 设计和测试化学抑制剂以阻止调节的酶的协作研究 关键的病毒PTM，不仅将为病毒的宿主控制提供独特的机械洞察力 复制，但也将为开发新的抗病毒药奠定基础 病毒传染病。