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，从功能上针对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维病毒学家、结构生物学家和结构化学家组成的团队之间的密切合作互动来实现。由Thilo Stehle教授领导的项目1将重点放在病毒上对与宿主细胞表面相互作用至关重要的部位的结构特征和识别上。由沃尔特·阿特伍德教授领导的第二个项目将在病毒中引入基于这些结构的定点突变，并从功能上表征这些突变体在组装、DNA包装、细胞结合、细胞穿透和感染方面的缺陷。由Dale Mierke教授领导的#3项目将设计和合成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支持，该中心由米尔克和斯帕勒博士领导。一个行政核心将设在布朗大学。该计划的总体目标是利用结构信息来获得有效、无毒和生物可用的精致特异的多瘤病毒感染抑制剂。团队中的三个主要研究人员建立了强大的工作协作，支持这一应用的坚实的初步数据证明了这一点。

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 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.