Understanding BK virus in kidney transplantation

了解肾移植中的 BK 病毒

• 批准号: MR/X030997/1
• 负责人: Matthew Welberry Smith
• 金额: $ 44.69万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX030997%2F1
• 关键词: Understanding; BK; virus; kidney; transplantation

Each year, over 90,000 patients worldwide suffering from kidney disease receive a life transforming kidney transplant. These patients take immunosuppression medications to prevent rejection of the transplanted kidney, but those medications increase the risk of infection. Of growing importance in this regard is BK virus, a harmless virus in a healthy person, but one that can cause severe disease in kidney transplant patients.Uncontrolled BK infection can trigger serious damage to the kidney in a person taking immunosuppression, limiting transplant function and potentially leading to premature kidney loss and return to dialysis. There are no effective treatments for BK infection, other than reducing anti-rejection medications to allow the immune system to fight BK, which increases the risk of transplant rejection and loss.As kidney transplantation has become more complex over time, an increasing number of patients need strong immunosuppression combinations to prevent their kidney transplant from rejecting. This means the number of patients with kidney transplants affected by BK virus is expected to grow, For this reason it is increasingly important that we have a clear understanding of the molecular mechanisms of BK virus and use this to develop new treatments.BK virus is present in the vast majority of people by the time they are adults. We recently showed that a protein made by BK virus (called agnoprotein) forms a channel and that by a mechanism that we do not understand, this channel-forming ability is necessary to allow the virus to exit from infected cells - this is referred to as a "viroporin". Since the virus is present in almost every person receiving a kidney transplant, how it leaves the cells is thought to be critical to the problems it can cause for a kidney transplant.This project will examine the structure and function of agnoprotein in the way the virus leaves the cells and seek to identify targets for medications that could stop the BK virus from damaging the kidney transplant. Specific aims of the project are:1) Understand agnoprotein viroporin structure and function:o Determine the 3D molecular structure of the agnoprotein viroporin using advanced electron microscopyo Define molecular target sites in the structure creating a platform for functional analysis and for screening of compounds for the ability to disrupt the viroporin function2) Develop potent agnoprotein inhibitorso Use our novel structural knowledge of the agnoprotein viroporin to understand the binding of known low potency inhibitorso Use this information to screen virtual libraries of compounds for high potency inhibitors o Test these inhibitors in vitro and in cell culture models to generate a suite of compounds for further functional studies and potential future clinical use3) Validate viroporin function, and novel inhibitors in primary cell culture modelso Use two complementary cell culture systems to model the antiviral activity of the high potency inhibitor compoundsWe will work with expert collaborators in Structural Biology and Medicinal Chemistry, and other BK researchers who use different cell culture models, to ensure our results are robust and can be taken forward to find new treatments for BK virus.Ultimately, this will benefit patients by reducing the problems caused by BK virus, which will make kidney transplants affected by BK virus last longer.

每年，全世界有超过 90,000 名患有肾病的患者接受了改变生活的肾移植。这些患者服用免疫抑制药物来防止移植肾的排斥反应，但这些药物会增加感染的风险。在这方面，BK 病毒变得越来越重要，它是一种对健康人无害的病毒，但可以在肾移植患者中引起严重疾病。不受控制的 BK 感染可能会对服用免疫抑制剂的人的肾脏造成严重损害，从而限制移植功能和可能导致肾过早丧失并重新进行透析。对于 BK 感染，除了减少抗排斥药物，让免疫系统对抗 BK 之外，没有有效的治疗方法，这会增加移植排斥和丢失的风险。随着时间的推移，肾移植变得越来越复杂，越来越多的患者需要强有力的免疫抑制组合来防止肾移植排斥。这意味着受BK病毒影响的肾移植患者数量预计将增加，因此，我们清楚地了解BK病毒的分子机制并利用它来开发新的治疗方法变得越来越重要。BK病毒的存在绝大多数人在成年时就已经存在了。我们最近表明，BK 病毒产生的一种蛋白质（称为无视蛋白）形成了一个通道，并且通过一种我们不了解的机制，这种通道形成能力对于允许病毒从受感染的细胞中退出是必要的 - 这被称为“病毒孔蛋白”。由于几乎每个接受肾移植的人体内都存在这种病毒，因此它如何离开细胞被认为对其可能导致肾移植的问题至关重要。该项目将以病毒的方式检查无视蛋白的结构和功能离开细胞并寻找可以阻止 BK 病毒损害肾移植的药物靶点。该项目的具体目标是：1) 了解agno蛋白病毒孔蛋白的结构和功能：o 使用先进的电子显微镜确定agno蛋白病毒孔蛋白的3D分子结构o 定义结构中的分子靶位点，为功能分析和筛选化合物创建一个平台破坏病毒孔蛋白功能的能力2) 开发有效的无视蛋白抑制剂so 使用我们关于无视蛋白病毒孔蛋白的新颖结构知识来了解已知低效抑制剂的结合所以使用此信息来筛选化合物的虚拟库o 在体外和细胞培养模型中测试这些抑制剂，以生成一套化合物，用于进一步的功能研究和未来潜在的临床用途3) 在原代细胞培养模型中验证病毒孔蛋白功能和新型抑制剂o 使用两种互补的细胞培养系统建立高效抑制剂化合物的抗病毒活性模型我们将与结构生物学和药物化学领域的专家合作者以及使用不同细胞培养模型的其他 BK 研究人员合作，以确保我们的结果稳健并可以继续推进寻找针对BK病毒的新疗法。最终，这将通过减少BK病毒引起的问题使患者受益，这将使受BK病毒影响的肾移植持续更长时间。