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: 8304292
• 负责人: Walter J Atwood
• 金额: $ 116.08万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304292
• 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

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）：该项目汇集了一个由三位科学家组成的跨学科团队，他们具有独特的专业知识，可以功能性地靶向和抑制人类多瘤病毒感染。一般来说，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，即进行性多灶性脑白质病（PML）的病原体。大多数PML病例发生在艾滋病患者中，但最近PML也被证明发生在多发性硬化症患者中，这些患者接受有效的免疫调节药物治疗，抑制中枢神经系统的免疫监视。目前还没有直接针对这种病毒的药物，这个项目的一个主要目标是确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将专注于结构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点。由Walter Atwood教授领导的项目# 2将介绍基于这些结构的病毒位点特异性突变，并在功能上表征突变体在组装、DNA包装、细胞结合、细胞渗透和感染方面的缺陷。Dale Mierke教授领导的项目# 3将设计和合成化学化合物来对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。这些项目将由达特茅斯学院的一个化学合成中心提供支持。Mierke和Spaller。行政中心将设在布朗大学。该计划的总体目标是利用结构信息来获得有效、无毒和生物可利用的多瘤病毒感染的精细特异性抑制剂。团队中的三位主要研究人员已经建立了强有力的工作合作关系，支持该应用程序的可靠初步数据证明了这一点。