Virus Wars: Are E3-Targeted Therapies A New Hope?

病毒战争：E3 靶向疗法是新希望吗？

• 批准号: MR/T043482/1
• 负责人: Adam Fletcher
• 金额: $ 156.16万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT043482%2F1
• 关键词: Virus; Wars; E3; Targeted; Therapies

Viral infections are responsible for an unquantifiable amount of disease, death and socioeconomic burden around the world. Some viruses seem too evasive to vaccinate against and antiviral drugs ultimately fail because they cause resistance in their viral targets. There is an urgent need for new classes of antiviral medicines.The main objective of my research proposal is to fast-track the development of 'host-directed therapies', a promising alternative to antiviral drugs that target viral proteins.To do this, I first want to understand which are the relevant participants of a host cell's response to viral infection. A frequently held assumption is that cells regulate their enzymes simply by changing their relative abundance. We learn (and generally agree) that post-translational control is important, but measuring this has been much trickier than assessing gene expression or protein abundance, which have over time become a surrogate for 'activity'. A lab at the University of Dundee have designed an ingenious way to specifically measure the activity (rather than the abundance) of a particular class of enzyme that has profound importance in all aspects of cell biology - the 'E3 ubiquitin ligase' (E3).E3s act like 'sticker-guns', labelling other proteins with a small protein modification called ubiquitin. Ubiquitin-labelled proteins are most commonly sent to the cell's molecular waste disposal system for recycling. Some E3s are known to help viral infections progress (pro-viral) while others hinder the progression of infection (antiviral). Manipulating these activities could lead to new innovative therapies to control viral infections.The technology - called an 'Activity-based probe' (ABP) - works by mimicking the E3s main partner in life, the E2 ubiquitin conjugating (E2) enzyme. E2s bind transiently to active E3s in cells; an E2-based ABP binds irreversibly to E3s, trapping it and divulging its prior state of activation. So, using the ABP allows me to sort the 'wheat from the chaff' and discover which E3s we should be focusing on when we talk about 'host-directed therapy'.Three particularly pernicious infections which show few signs of abating are human immunodeficiency virus (HIV) and influenza A virus (IAV). HIV is a pandemic infection; IAV has the potential for pandemics. Using these two virus infections models, I will look for common and divergent 'molecular signatures' in the host's E3 activity response that might signpost the way to novel therapies. I will infect cells with a virus, and then send the ABP scouts inside the infected cell, where they reveal a panorama of E3 activity change during the course of infection. Identifying convergent molecular signatures in our cells might even signpost the way to broad-spectrum host-directed therapies.

病毒感染在全世界造成无法量化的疾病、死亡和社会经济负担。一些病毒似乎太过逃避，无法接种疫苗，抗病毒药物最终失败，因为它们会导致病毒靶点产生耐药性。我们迫切需要新的抗病毒药物。我的研究计划的主要目标是快速跟踪“宿主导向疗法”的发展，这是一种有前途的替代抗病毒药物的靶向病毒蛋白。为此，我首先想了解哪些是宿主细胞对病毒感染的反应的相关参与者。一个经常持有的假设是，细胞调节其酶简单地通过改变它们的相对丰度。我们了解到（并且普遍同意）翻译后控制是重要的，但是测量这一点比评估基因表达或蛋白质丰度要棘手得多，随着时间的推移，基因表达或蛋白质丰度已经成为“活性”的替代品。邓迪大学的一个实验室设计了一种巧妙的方法来专门测量一种特殊类型的酶的活性（而不是丰度），这种酶在细胞生物学的各个方面都具有深远的重要性-“E3泛素连接酶”（E3）。泛素标记的蛋白质通常被送到细胞的分子废物处理系统进行回收。已知一些E3有助于病毒感染的进展（前病毒），而另一些则阻碍感染的进展（抗病毒）。操纵这些活性可能会导致新的创新疗法来控制病毒感染。这项技术-称为“基于活性的探针”（ABP）-通过模拟E3在生命中的主要伴侣，E2泛素结合（E2）酶来工作。E2与细胞中的活性E3短暂结合;基于E2的ABP与E3不可逆地结合，捕获它并泄露其先前的活化状态。因此，使用ABP可以让我从谷壳中挑选出小麦，并发现当我们谈论“宿主定向治疗”时，我们应该关注哪些E3。三种特别有害的感染几乎没有减弱的迹象，它们是人类免疫缺陷病毒（HIV）和甲型流感病毒（IAV）。艾滋病毒是一种大流行性感染; IAV有可能造成大流行。使用这两种病毒感染模型，我将寻找共同的和不同的“分子签名”在主机的E3活性反应，可能标志着新的治疗方法。我将用病毒感染细胞，然后将ABP侦察机送入感染细胞内，在那里它们显示了感染过程中E3活性变化的全景。在我们的细胞中识别会聚的分子特征甚至可能为广谱宿主导向疗法指明方向。