STRUCTURE DETERMINATION OF VIRAL NUCLEOPROTEIN COMPLEXES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 本实验室主要从事病毒核衣壳结构的研究。我们感兴趣的是结构是如何参与负链RNA病毒（NSRV）的组装和功能。NSRVs包括一些最危险的人类病原体，如埃博拉病毒、狂犬病病毒、禽流感病毒和麻疹病毒。该建议是我们以前和继续与水泡性口炎病毒（VSV）的病毒核衣壳（N）蛋白的工作的延伸。N与90-mer RNA复合的十聚体结构已经完成。目前，N-RNA与其他VSV蛋白的复合物是研究的重点。此外，我们正在继续扩展弹状病毒家族以外的研究，以研究其他三个NSRV家族的核衣壳蛋白，正粘病毒科，副粘病毒科和布尼亚病毒科（分别为流感病毒，RSV和布尼亚韦拉病毒）。流感核蛋白（NP）的结构研究与针对病毒糖蛋白HA的抑制剂的设计相辅相成。我们已经发现了一类新的融合抑制剂，其对流感病毒具有有效且不可逆的抑制作用。我们还继续研究HIV CA/抑制剂复合物。这些抑制剂被设计为破坏病毒组装和成熟。在这里，我们希望将最初的命中转化为优化的药物线索，并最终转化为第二代候选药物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our lab is focused on the study of virus nucleocapsid structure. We are interested in how structure is involved with assembly and function of negative strand RNA viruses (NSRVs). The group of NSRVs includes some of the most dangerous human pathogens, such as Ebola, rabies, avian influenza, and measles viruses. This proposal is an extension of our previous and continued work with the viral nucleocapsid (N) protein of vesicular stomatitis virus (VSV). The decameric structure of N complexed with a 90-mer of RNA has been completed. Now, complexes between the N-RNA and other VSV proteins are the focus of study. Additionally, we are continuing to expand beyond the Rhabdovirus family, to study nucleocapsid proteins of three other NSRV families, Orthomyxoviridae, Paramyxoviridae and Bunyaviridae (influenza virus, RSV and Bunyamwera virus, respectively). The structural study of the influenza nucleoprotein (NP) is complimented with the design of inhibitors against the viral glycoprotein HA. We have found a novel class of fusion inhibitors that have a potent and irreversible inhibitory effect on influenza viruses. We also continue the study of HIV CA/inhibitor complexes. These inhibitors are designed disrupt viral assembly and maturation. Here we look to transform initial hits into optimized drug leads and ultimately into second generation drug candidates.