Structure-function based development of JC virion specific antagonists for PML

描述(由申请者提供)：该计划项目汇集了一个由三名具有独特专业知识的科学家组成的跨学科团队，在功能上进行靶向和抑制 人类多瘤病毒感染。一般的多瘤病毒，特别是人类多瘤病毒，已被证明利用不同的宿主细胞碳水化合物和蛋白质来感染目标细胞和组织。人类多瘤病毒JCV是一种致命的中枢神经系统脱髓鞘疾病的病原体，称为进行性多灶性白质脑病(PML)。大多数PML病例发生在艾滋病患者中，但最近研究表明，PML也发生在接受有效免疫调节药物治疗的多发性硬化症患者中，这些药物抑制了中枢神经系统的免疫监视。目前还没有直接针对病毒的药物正在研发中，该计划的一个主要目标是识别能够直接抑制病毒感染的化合物。这一目标将通过一个由多病毒学家、结构生物学家和分子遗传学家/病毒学家组成的团队之间的密切合作互动来实现。由Thilo Stehle教授领导的项目1将侧重于从结构上表征和识别病毒上对与宿主细胞表面相互作用至关重要的位置。由沃尔特·阿特伍德教授领导的项目2将在病毒中引入基于这些结构的定点突变，并从功能上描述突变的特征。项目2还将进一步开发在该计划项目的第1-4年中确定的药物先导。项目#3由Dr。 Dan DiMaio将对JCV入侵宿主细胞的关键因素进行基因筛查。这些项目将得到布朗大学由Gretchen Gee博士领导的病毒和伪病毒生产核心的支持。一个行政核心将设在布朗大学。该计划的总体目标是使用结构信息和高通量基因筛查来确定可以利用来抑制多瘤病毒感染的因素和靶点。团队中的三个主要调查人员建立了强有力的工作协作，坚实的初步数据和支持这一应用程序的许多联合出版物证明了这一点。

DESCRIPTION (provided by applicant): This program project brings together an interdisciplinary team of three scientists with unique expertise to functionally target and inhibit human polyomavirus infections. The polyomaviruses in general, and the human polyomaviruses in particular, have been shown to utilize distinct host cell carbohydrates and proteins to infect target cells and tissues. The human polyomavirus JCV is the causative agent of a fatal central nervous system demyelinating disease known as progressive multifocal leukoencephalopathy (PML). The majority of PML cases occur in patients with AIDS but recently PML has also been shown to occur in multiple sclerosis patients being treated with potent immunomodulatory drugs that inhibit immunosurveillance of the CNS. There are currently no drugs in the pipeline that target the virus directly and a major goal of this program is to identify compounds capable of directly inhibiting virus infection. This goal will be accomplished by close collaborative interactions between a team consisting of a polyomavirologist, a structural biologist, and a molecular geneticist/virologist. Project # 1 led by Professor Thilo Stehle will focus on structuraly characterizing and identifying sites on the virus that are critical for interacting with host cell surfaces. Project # 2 led by Professor Walter Atwood will introduce site-specific mutations in the virus based on these structures and functionally characterize the mutants. Project #2 will also further develop a drug lead identified in years 1-4 of this program project. Project # 3 led by Dr. Dan DiMaio will conduct genetic screens for factors that are critical for JCV invasion of host cells. The projects will be supported by a virus and pseudovirus production core at Brown University headed by Dr. Gretchen Gee. An administrative core will be housed at Brown University. The overall goal of this program is to use structural information and high throughput genetic screens to identify factors and targets that can be exploited to inhibit polyomavirus infection. The three major investigators on the team have built a strong working collaboration that is evidenced by the solid preliminary data and numerous joint publications that support this application.