P1: STEM REGION OF ENVELOPE PROTEIN OF DENGUE VIRUS AND RE-EMERGING FLAVIVIRUSES

该子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者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， NCRR赠款不直接向子项目或子项目工作人员提供资金。 已经做出了相当大的努力来开发针对蚊媒黄病毒（例如登革热病毒（DENV）、西尼罗河病毒（WNV）和日本脑炎病毒（JEV））的药物。然而，到目前为止，还没有这样的抗病毒药物可用。越来越多的证据表明，这些病毒的外壳或包膜蛋白的所谓茎区的特定区域参与病毒进入和病毒组装。茎含有几个高度保守的氨基酸在不同的黄病毒。我们推测这些高度保守的氨基酸在病毒进入和病毒组装中起重要作用。本研究的目的是分析DENV和其他医学上重要的黄病毒的茎区，以寻找新的靶点，从而开发抗病毒药物。 在目的1中，我们将研究高度保守的氨基酸在登革病毒血清型4的进入和组装中的作用。在目的2中，我们将研究DENV血清型4的进入和组装的损伤机制。目的3：研究高度保守的氨基酸在其他DENV血清型以及WNV和JEV进入和组装中的作用。 高度保守的氨基酸在病毒组装和进入过程中的作用的表征将导致对黄病毒复制的分子机制的新见解。反过来，这些新知识将导致新的抗病毒药物的开发，以减少与DENV和其他黄病毒引起的疾病相关的人类痛苦和死亡。

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. Considerable effort has been made to develop drugs against mosquito-borne flaviviruses, such as dengue virus (DENV), West Nile virus (WNV) and Japanese encephalitis virus (JEV). However, to date no such antiviral drugs are available. Growing evidence suggests that a particular area of the so-called stem region of the outer coating, or envelope protein, of these viruses is involved in virus entry and virus assembly. The stem contains several highly conserved amino acids among different flaviviruses. We conjecture that these highly conserved amino acids play important roles in virus entry and virus assembly. The objective of this study is to analyze the stem region of DENV and other medically important flaviviruses for novel targets that would lead to the development of antiviral drugs. In Aim 1, we will investigate the role of the highly conserved amino acids on the entry and assembly of DENV serotype 4. In Aim 2, we will investigate the mechanisms of impairment on the entry and assembly of DENV serotype 4. And in Aim 3, we will investigate the role of the highly conserved amino acids on the entry and assembly of other DENV serotypes, as well as WNV and JEV. Characterization of the roles of the highly conserved amino acids on virus assembly and entry would lead to new insights about the molecular mechanisms of flavivirus replication. In turn, this new knowledge will lead to the development of new antiviral drugs to reduce the human suffering and deaths associated with diseases caused by DENV and other flaviviruses.