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9万名肾病患者接受了改变生命的肾脏移植手术。这些患者服用免疫抑制药物以防止移植肾的排斥反应，但这些药物增加了感染的风险。在这方面越来越重要的是BK病毒，这是一种对健康人无害的病毒，但可能会导致肾移植患者的严重疾病。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，限制移植功能，并可能导致过早失去肾脏并重新进行透析。目前还没有有效的治疗BK感染的方法，除了减少抗排斥药物以使免疫系统能够对抗BK，这会增加移植排斥和损失的风险。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大的免疫抑制组合来防止他们的肾移植排斥反应。这意味着受BK病毒影响的肾移植患者的数量预计会增加，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病毒在绝大多数人成年时就已经存在了。我们最近发现，BK病毒制造的一种蛋白质(称为无核蛋白)形成了一个通道，通过一种我们不知道的机制，这种通道形成能力是允许病毒从受感染的细胞中退出所必需的-这被称为“病毒孔蛋白”。由于BK病毒几乎存在于每个接受肾移植的人身上，因此它如何离开细胞被认为是导致肾移植问题的关键。该项目将检查病毒离开细胞的方式中未知蛋白的结构和功能，并寻求确定药物的靶点，以阻止BK病毒破坏肾脏移植。该项目的具体目标是：1)了解无核蛋白病毒孔蛋白的结构和功能：利用先进的电子显微镜确定无核蛋白病毒孔蛋白的三维分子结构在结构中定义分子靶位为功能分析和筛选化合物提供一个平台以破坏病毒孔蛋白的功能2)开发有效的无核细胞蛋白抑制剂因此利用我们对无核细胞蛋白的新的结构知识来了解已知的低效抑制物的结合所以利用这些信息来筛选高效抑制物化合物的虚拟文库在体外和在细胞培养模型中测试这些抑制物以产生一套化合物用于进一步的功能研究和未来潜在的临床应用3)验证病毒孔蛋白的功能我们将与结构生物学和药物化学领域的专家合作者以及其他使用不同细胞培养模型的BK研究人员合作，以确保我们的结果是可靠的，并可以在此基础上寻找治疗BK病毒的新方法。最终，这将通过减少BK病毒造成的问题而使患者受益，这将使受BK病毒影响的肾移植存活更长时间。