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

基于结构-功能的 JC 病毒颗粒特异性 PML 拮抗剂的开发

• 批准号: 8789634
• 负责人: Walter J Atwood
• 金额: $ 133.39万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789634
• 关键词: Acquired Immunodeficiency Syndrome; Brain Diseases; Capsid; Carbohydrates; Cell surface; Cells; Collaborations; Data; Development; Disease; Funding; Genes; Genetic; Genetic Screening; Goals; Head; Housing; Human; Immunologic Monitoring; Infection; Invaded; Joints; Lead; Life Cycle Stages; Molecular; Multiple Sclerosis; Mutation; Patients; Pharmaceutical Preparations; Phase; Polyomavirus; Polyomavirus Infections; Production; Program Development; Progressive Multifocal Leukoencephalopathy; Proteins; Publications; Research Personnel; Scientist; Site; Solid; Staging; Structural Biologist; Structure; Testing; Therapeutic; Tissues; Universities; Viral; Virion; Virus; Virus Diseases; Work; base; cellular targeting; central nervous system demyelinating disorder; immune function; mutant; nervous system disorder; novel; prevent; professor; programs; public health relevance; tool

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.

描述（由申请人提供）：该计划项目汇集了一个由三名科学家组成的跨学科团队，他们具有独特的专业知识，可以在功能上靶向和抑制 人类多瘤病毒感染。一般而言，多瘤病毒，特别是人多瘤病毒，已显示利用不同的宿主细胞碳水化合物和蛋白质来感染靶细胞和组织。人多瘤病毒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AIDS患者中，但最近发现PML也发生在接受强效免疫调节药物治疗的多发性硬化症患者中，这些药物可抑制CNS的免疫监视。目前还没有直接靶向病毒的药物，该计划的主要目标是鉴定能够直接抑制病毒感染的化合物。这一目标将通过由多瘤病毒学家、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协作互动来实现。由Thilo Stehle教授领导的项目#1将专注于结构表征和识别病毒上与宿主细胞表面相互作用的关键位点。由Walter Atwood教授领导的2号项目将根据这些结构在病毒中引入位点特异性突变，并对突变体进行功能表征。项目#2还将进一步开发本项目第1-4年确定的药物先导产品。项目#3由博士领导。 Dan DiMaio将对JCV入侵宿主细胞的关键因素进行遗传筛选。这些项目将得到由Gretchen Gee博士领导的布朗大学病毒和假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遗传筛选来鉴定可用于抑制多瘤病毒感染的因子和靶标。该团队的三位主要研究人员已经建立了强大的工作合作，这一点可以从支持该应用的坚实的初步数据和众多联合出版物中得到证明。