"Plugging the holes in COVID-19 therapy"

“填补 COVID-19 治疗中的漏洞”

• 批准号: 2602657
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2602657
• 关键词: Plugging; holes; COVID; 19; therapy

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2), has claimed over 1.4 million lives, infected almost 60 million people and caused profound morbidity and socioeconomic damage worldwide.Clinical management of severe disease has improved and recent vaccine trials are highly encouraging. However, a significant number of people may be unable to either receive or respond to a vaccine due to underlying immunological issues. Unfortunately, trials repurposing existing drugs as SARS-CoV2 antivirals have yet to yield convincing therapies. One overlooked, but essential drug target in SARS-CoV2 is the envelope (E) protein, which forms a virus-encoded ion channel, or "viroporin" that plays an essential role during the formation of infectious virus particles and also how they infect naïve cells. In addition, E is thought to interfere with host inflammatory responses. Thus, drugs capable of blocking E function could combat COVID-19 on two distinct fronts.We have worked on viroporins from several clinically important viruses, including hepatitis C virus, pandemic influenza and Zika virus, for many years. We use and generate structural information about channel complexes to help design and select small molecules as potential antivirals, but which also serve as tools to understand the fundamental biology of these proteins.Now, turning to SARS-CoV2 E, we have already identified existing drugs that potently block its activity, and we hope to rapidly advance these as new therapies. However, existing structures for E channels aren't consistent with drug binding, likely due to their being only partial domains or solved in unnatural environments.The aims of this PhD project, therefore, are:1. To solve the full atomic structure of SARS-CoV2 E channels in membranes using cryo-EM2. To use this structure to develop potent new antivirals targeting E channel activity3. To exploit new drugs to understand how E influences SARS-CoV2 during infectionThe student on this project will have a unique opportunity to integrate molecular virology, structural biology and medicinal chemistry to address the most profound challenge to human health in over a century. Training and using state-of-the-art facilities such as the Titan Krios electron microscopes, high-powered computing, advanced bio-imaging and Biological Safety Level (BSL) 3 containment laboratories will ensure all aspects of the project are able to thrive and generate meaningful, publication quality results. The student will gain both interdisciplinary and quantitative skills, taking an increasingly leading role as the project continues and develops.

由严重急性呼吸综合征2型冠状病毒引起的2019年新冠肺炎大流行已夺走140多万人的生命，感染近6000万人，在全球范围内造成严重的发病率和社会经济损失。严重疾病的临床管理得到改善，最近的疫苗试验令人鼓舞。然而，由于潜在的免疫学问题，相当数量的人可能无法接种疫苗或对疫苗产生反应。不幸的是，将现有药物重新用作SARS-CoV2抗病毒药物的试验尚未产生令人信服的疗法。SARS-CoV2的一个被忽视的但基本的药物靶标是包膜(E)蛋白，它形成了病毒编码的离子通道，或称“病毒素”，在感染性病毒颗粒的形成以及它们如何感染幼稚细胞的过程中发挥了关键作用。此外，E被认为可以干扰宿主的炎症反应。因此，能够阻断E功能的药物可以在两个不同的战线上对抗新冠肺炎。我们多年来一直在研究几种临床重要病毒的病毒孔蛋白，包括丙型肝炎病毒、大流行性流感和寨卡病毒。我们使用和生成关于通道复合体的结构信息来帮助设计和选择小分子作为潜在的抗病毒药物，但这些小分子也可以用作了解这些蛋白质的基本生物学的工具。现在，转向SARS-CoV2 E，我们已经确定了能够有效阻断其活性的现有药物，我们希望迅速将这些药物作为新的疗法推进。然而，现有的E通道结构与药物结合并不一致，这可能是由于它们只是部分结构域或在非自然环境中解决的。因此，本博士项目的目的是：1.使用Cryo-EM2解决SARS-CoV2 E通道在膜中的完整原子结构。利用这种结构来开发针对E通道活性的有效的新的抗病毒药物。开发新药以了解E在感染过程中如何影响SARS-CoV2这个项目的学生将有一个独特的机会将分子病毒学、结构生物学和药物化学结合起来，以应对一个多世纪以来对人类健康最深刻的挑战。培训和使用最先进的设施，如泰坦Krios电子显微镜、高性能计算、先进的生物成像和生物安全水平(BSL)3遏制实验室，将确保项目的所有方面都能蓬勃发展，并产生有意义的、出版质量的成果。学生将获得跨学科和定量的技能，随着项目的继续和发展，发挥越来越重要的作用。