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: 10662495
• 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/10662495
• 关键词: Address; Antiviral Agents; Antiviral Therapy; Biochemical; Cells; Chemicals; Communicable Diseases; Creativeness; Deacetylase; Deubiquitinating Enzyme; Development; Disease; 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; future outbreak; future pandemic; influenzavirus; inhibitor; innovation; insight; novel; pathogenic virus; prevent; reverse genetics; therapeutic RNA; ubiquitin isopeptidase; 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.

项目概要 在过去的几十年里，对抗病毒感染的传统方法 疾病的目标是病毒本身，在大多数情况下通过阻断病毒编码 病毒复制所需的酶，或阻止病毒进入宿主细胞的酶。 这些方法的主要警告之一是病毒容易突变的能力 并对这些经典类型的抗病毒疗法产生耐药性。事实上，这是一种。 RNA病毒感染的治疗存在严重问题，例如HIV或流感病毒，这些病毒 众所周知，它们会迅速突变，从而逃避传统的抗病毒药物的攻击。 方法旨在针对特定病毒，因此对任何新病毒无效 未来可能出现的病毒，无法预测下一个会是什么病毒 因此，迫切需要开发针对病毒的新方法。 病原体，这需要创造性和创新性的研究。 与人类蛋白质一样，病毒蛋白质也会经历翻译后修饰 （PTM）在病毒生命周期中的调节和正常功能在大多数情况下，是病毒 PTM。 受到人类酶的动态调节，例如激酶/磷酸酶、泛素 E3 连接酶/去泛素化酶，或乙酰基转移酶/去乙酰化酶。 在控制病毒复制和致病能力方面发挥着重要作用。 该提案的总体目标是全面绘制“病毒 PTMome”图谱，以识别 我们将结合蛋白质组学对病毒复制和发病机制至关重要的 PTM。 筛选和分子病毒学方法，包括带有切割的反向遗传学技术 这将使我们能够进行分子、生物化学和生物物理研究。 表征病毒 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制中的作用，与这种强大的方法相结合。 合作研究设计和测试化学抑制剂来阻断调节酶 关键的病毒 PTM，不仅可以提供对病毒宿主控制的独特机制见解 复制，但也将为开发新的抗病毒药物奠定基础 病毒性传染病。

项目成果

Acetylation of the NS3 helicase by KAT5γ is essential for flavivirus replication.

KAT5γ 对 NS3 解旋酶的乙酰化对于黄病毒复制至关重要。

• DOI: 10.1016/j.chom.2023.06.013
• 发表时间: 2023-07-01
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Taryn M. Serman;C. Chiang;Guanqun Liu;Zuberwasim Sayyad;S. P;ey;ey;M. Volcic;Haejeong Lee;Santoshi Muppala;D. Acharya;C. Goins;S. Stauffer;K. Sparrer;Michaela U. Gack
• 通讯作者: Michaela U. Gack