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

基本信息

批准号：
8512814
负责人：
Walter J Atwood
金额：
$ 111.79万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512814
关键词：
Acquired Immunodeficiency Syndrome Adenoviruses Affinity American Cancer Society Architecture Area Attention Binding Bioavailable Biological Biology California Cancer Center Cancer Center Planning Grant Carbohydrates Cell Communication Cell surface Cells Chemicals Chemistry Collaborations Combinatorial Synthesis Complement Complex Core Facility Cyclic Peptides Cyclization DNA Packaging DNA Tumor Viruses Data Defect Development Diversity Library Elements Faculty G-Protein-Coupled Receptors Ganglioside GM1 Genomics Goals Head Health Housing Human Immunologic Monitoring Infection JC Virus Journals Laboratories Libraries Ligands Manuscripts Marshal Measles virus Methodology Methods Modeling Molecular Molecular Structure Molecular Virology Molecular Weight Multiple Sclerosis Mutation NMR Spectroscopy Oligosaccharides Patients Penetration Peptides Pharmaceutical Preparations Polyomaviridae Polyomavirus Polyomavirus Infections Positioning Attribute Postdoctoral Fellow Prevention Progressive Multifocal Leukoencephalopathy Property Protein-Carbohydrate Interaction Proteins Publishing Qualifying Receptor Cell Reovirus Research Research Personnel Resolution Role Salinum Science Scientist Sialic Acids Side Signal Transduction Simian virus 40 Site Solid Solutions Specificity Structural Biologist Structural Chemistry Structure System Texas Tissues Training Transgenic Organisms United States National Institutes of Health Universities Virion Virus Virus Diseases Virus Receptors Work alpha-Defensins analog austin base central nervous system demyelinating disorder chemical synthesis college design experience graduate student inhibitor/antagonist meetings mouse polyomavirus mutant novel professor programs protein protein interaction receptor receptor coupling serotonin receptor small molecule libraries structural biology success therapy development virology

项目摘要

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 structural chemist. Project # 1 led by Professor Thilo Stehle will focus on structurally 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 for defects in assembly, DNA packaging, cell binding, cell penetration, and infection. Project # 3 led by Professor Dale Mierke will design and synthesize chemical compounds to antagonize virus host cell interactions. These compounds will be functionally screened by Project # 2. The projects will be supported by a chemical synthesis core at Dartmouth College headed by Drs. Mierke and Spaller. An administrative core will be housed at Brown University. The overall goal of this program is to use structural information to derive exquisitely specific inhibitors of polyomavirus infection that are potent, nontoxic, and bioavailable. The three major investigators on the team have built a strong working collaboration that is evidenced by the solid preliminary data supporting this application.

描述（由申请人提供）：该计划项目汇集了由三名科学家组成的跨学科团队，他们拥有独特的专业知识，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。人类多瘤病毒 JCV 是致命的中枢神经系统脱髓鞘疾病（称为进行性多灶性白质脑病 (PML)）的病原体。大多数 PML 病例发生在 AIDS 患者中，但最近也显示 PML 也发生在接受抑制中枢神经系统免疫监视的强效免疫调节药物治疗的多发性硬化症患者中。目前尚无直接针对病毒的药物正在研发中，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、结构生物学家和结构化学家组成的团队之间的密切合作来实现。由 Thilo Stehle 教授领导的项目#1将重点关注病毒的结构特征和识别位点，这些位点对于与宿主细胞表面相互作用至关重要。由 Walter Atwood 教授领导的项目 #2 将根据这些结构引入病毒中的位点特异性突变，并在功能上表征突变体的组装、DNA 包装、细胞结合、细胞渗透和感染方面的缺陷。由 Dale Mierke 教授领导的项目#3将设计和合成化合物来拮抗病毒宿主细胞的相互作用。这些化合物将由项目 #2 进行功能筛选。这些项目将得到达特茅斯学院化学合成核心的支持，该核心由 Drs.米尔克和斯帕尔。行政核心将设在布朗大学。该项目的总体目标是利用结构信息来衍生出有效、无毒且具有生物利用度的多瘤病毒感染的精确特异性抑制剂。该团队的三位主要研究人员建立了强有力的工作合作，支持该应用的可靠初步数据证明了这一点。