Influenza nucleoprotein interactions

流感病毒仍然是一个未得到满足的健康问题。尽管病毒是通过每年接种疫苗来控制的，但这些 表现出不同的疗效，疫苗生产缓慢意味着疫苗在新兴市场期间无法获得 大流行。抗病毒药物可以阻止流感大流行，但随着时间的推移，抗病毒药物会变得无效，因为 抗性病毒的选择。这些事实突出表明，有必要确定新的发展目标 对抗新出现的流感、控制流感相关疾病和提高人类健康水平的抗病毒疗法 健康。迫切需要发现新的分子靶点并生产新的抗病毒疗法来对抗 流感病毒，以防止新出现的大流行。我们的长期目标是发现多个可以 联合利用以阻止流感病毒。我们的目标是确定流感核蛋白的特征 (NP)对流感RNA表达至关重要的相互作用。NP是功能性病毒的重要组成部分 核糖核蛋白(VRNP)，负责病毒mRNA转录和RNA基因组复制。最近一段时间 FDA批准了第一种针对这种流感病毒复合体的抗病毒药物。XOFLUZA是一种核酸内切酶抑制剂 靶向vRNP复合体的流感PA蛋白，有望迅速抑制流感感染。 这种新的抗病毒药物所针对的活性是近40年前通过公共资助的研究发现的。 (克鲁格，1981)，并举例说明了我们提议的研究的重要性。我们的工作是互补的，而且 重点研究vRNP的核蛋白。我们的中心假设是，阐明分子相互作用 对流感RNA表达至关重要的基因将识别新的抗病毒靶点。有理由认为，将目标对准高度 保守的病毒蛋白不太可能导致耐药性的进化，特别是当保守的靶点 在多个地点受到攻击。一旦更好地理解，对病毒RNA表达至关重要的相互作用将揭示 预防新出现的流感病毒大流行的新方法。测试我们的中心假设并实现我们的 总体目标，我们将追求以下具体目标：1)表征流感核蛋白 VRNP功能所必需的相互作用和2)定义流感核蛋白与非 结构蛋白1.拟议的研究具有重要意义，因为我们将识别多个抗病毒靶点 在NP的保守区内，推测不太容易产生抗药性。建议数 研究具有创新性，因为它将确定抑制流感的新靶点，可能包括宿主因素 它们与NP相互作用，但为宿主提供多余的功能。这项研究将促进人们对 流感病毒的生理学，并提供可用于支持的基本信息 开发新的抗流感疗法，增进人类健康。

Influenza virus remains an unmet health issue. Although the virus is controlled with annual vaccines, these exhibit variable efficacy, and slow vaccine production means vaccines are not available during an emerging pandemic. Antivirals can stunt an influenza pandemic, but antivirals become ineffective over time due to selection of resistant viruses. These facts highlight the need to identify novel targets for development of new antiviral therapies to combat emerging influenza, control influenza-related disease, and enhance human health. There is urgent need to discover new molecular targets and produce novel antiviral therapies against influenza virus to prevent an emerging pandemic. Our long-term goal is to discover multiple targets that can be exploited in combination to block influenza viruses. Our objective is to characterize influenza nucleoprotein (NP) interactions essential for influenza RNA expression. NP is an essential component of the functional viral ribonucleoprotein (vRNP), responsible for viral mRNA transcription and RNA genome replication. Recently the FDA approved the first antiviral to target this influenza-virus complex. XOFLUZA is an endonuclease inhibitor targeting influenza PA protein of the vRNP complex and has great promise to inhibit influenza infection rapidly. The activity targeted in this new antiviral was discovered via publicly funded research nearly 40 years ago (Krug, 1981) and exemplifies the importance of our proposed research. Our work is complementary and focuses on the nucleoprotein of the vRNP. Our central hypothesis is that elucidating molecular interactions essential for influenza RNA expression will identify novel antiviral targets. It is reasoned that targeting a highly conserved viral protein is less likely to result in evolution of resistance, particularly when the conserved target is attacked at multiple sites. Once better understood, interactions essential to viral RNA expression will reveal novel ways of preventing an emerging influenza virus pandemic. To test our central hypothesis and attain our overall objective, we will pursue the following specific aims: 1) Characterize influenza nucleoprotein interactions essential for vRNP function and 2) Define influenza nucleoprotein interaction with non- structural protein 1. The proposed research is significant because we will identify multiple antiviral targets within conserved regions of NP, reasoned to be less prone to the development of resistance. The proposed research is innovative because it will identify novel targets to inhibit influenza, possibly including host factors that interact with NP but serve redundant functions for the host. This research will advance knowledge of the physiology of influenza virus and provide fundamental information that can be harnessed to support development of new anti-influenza therapies and enhance human health.