STRUCTURE DETERMINATION OF VIRAL NUCLEOPROTEIN COMPLEXES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本实验室致力于病毒核衣壳结构的研究。我们感兴趣的是结构如何与负链RNA病毒(NSRV)的组装和功能有关。NSRV组包括一些最危险的人类病原体，如埃博拉病毒、狂犬病、禽流感和麻疹病毒。这项建议是我们先前和继续研究水疱性口炎病毒(VSV)的病毒核衣壳(N)蛋白工作的延伸。N与90聚体RNA络合的十聚体结构已经完成。目前，N-RNA与其他VSV蛋白之间的复合体是研究的重点。此外，我们正在继续扩展到横纹病毒家族之外，研究另外三个NSRV家族的核衣壳蛋白，它们是正粘病毒科、副粘病毒科和布尼亚病毒科(分别是流感病毒、呼吸道合胞病毒和布尼亚病毒科)。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。我们发现了一类新型的融合抑制剂，它对流感病毒具有强大的不可逆转的抑制作用。我们还继续对HIV CA/抑制剂复合体的研究。这些抑制剂旨在破坏病毒的组装和成熟。在这里，我们希望将最初的热门药物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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.