Influenza nucleoprotein interactions

流感核蛋白相互作用

• 批准号: 10321202
• 负责人: Laura Lynn Newcomb
• 金额: $ 11.03万
• 依托单位: CALIFORNIA STATE UNIV SAN BERNARDINO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-08 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321202
• 关键词: Amino Acids; Antiviral Agents; Antiviral Response; Antiviral Therapy; Binding; Cell Culture Techniques; Cell Nucleus; Complex; Development; Disease; Engineering; Epitopes; Essential Amino Acids; Event; Evolution; Exhibits; FDA approved; Funding; Gene Expression; Genetic Transcription; Genome; Goals; Health; Human; Influenza; Influenza A virus; Integration Host Factors; Interferons; Knowledge; Messenger RNA; Molecular; Molecular Target; N-terminal; Nonstructural Protein; Nucleic Acid Binding; Nucleoproteins; Outcome; Physiology; Proteins; RNA; RNA Viruses; RNA chemical synthesis; RNA replication; Recombinants; Research; Research Design; Resistance; Resistance development; Ribonucleoproteins; Role; Site; Testing; Time; Vaccine Production; Vaccines; Viral; Viral Genes; Viral Proteins; Virus; Virus Replication; Work; anti-influenza; combat; combinatorial; design; endonuclease; influenza infection; influenzavirus; inhibitor; innovation; mutant; novel; pandemic disease; pandemic influenza; pressure; prevent; protein complex; reconstitution; resistant strain; response; small molecule inhibitor; success; targeted treatment; viral RNA

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.

流感病毒仍然是一个未得到解决的健康问题。虽然每年接种疫苗可以控制病毒， 疫苗生产缓慢意味着在新出现的疾病期间无法获得疫苗。 流行病抗病毒药物可以阻止流感大流行，但随着时间的推移，抗病毒药物变得无效， 选择抗性病毒。这些事实突出表明，需要确定新的目标，以开发新的 抗病毒治疗，以对抗新出现的流感，控制流感相关疾病，并提高人类 健康目前迫切需要发现新的分子靶点，并产生新的抗病毒疗法， 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目标， 联合使用来阻止流感病毒。我们的目标是表征流感核蛋白 (NP)流感病毒RNA表达所必需的相互作用。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 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复合物的流感PA蛋白，并且具有快速抑制流感感染的巨大前景。 这种新的抗病毒药物的活性是近40年前通过公共资助的研究发现的 (Krug，1981），并强调了我们提出的研究的重要性。我们的工作是互补的， 重点是vRNP的核蛋白。我们的中心假设是阐明分子相互作用 流感病毒RNA表达所必需的基因将鉴定新的抗病毒靶点。有理由认为，针对一个高度 保守的病毒蛋白不太可能导致抗性的进化，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，病毒RNA表达所必需的相互作用将揭示 预防新出现的流感病毒大流行的新方法。为了验证我们的核心假设， 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流感病毒核蛋白的相互作用。 结构蛋白1。这项拟议中的研究意义重大，因为我们将确定多个抗病毒靶点 在NP的保守区域内，被认为不太容易产生抗性。拟议 这项研究具有创新性，因为它将确定抑制流感的新靶点，可能包括宿主因素 与NP相互作用，但为宿主提供冗余功能。这项研究将进一步了解 流感病毒生理学，并提供基本信息， 开发新的抗流感疗法，增进人类健康。