Targeting the NS1 Protein for the Development of Influenza Virus Antivirals

以 NS1 蛋白为靶点开发流感病毒抗病毒药物

• 批准号: 7913042
• 负责人: Robert M Krug
• 金额: $ 99.95万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-17 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913042
• 关键词: Affinity; Africa; Amantadine; Amantadine resistance; Animal Experiments; Animals; Antiviral Agents; Asia; Binding; Binding Sites; Biological Assay; Birds; Cell physiology; Cells; Cercopithecine Herpesvirus 1; Chemicals; Collaborations; Complex; Computers; Custom; Databases; Development; Diagnostic; Double-Stranded RNA; Drug Delivery Systems; Epidemic; Europe; Ferrets; Goals; Human; Influenza; Influenza A Virus, H5N1 Subtype; Influenza A virus; Influenza B virus; Institutes; Ion Channel Protein; Laboratories; Lead; Libraries; Ligands; Lung diseases; Measures; Medical; Methods; Mus; N-terminal; Neuraminidase; Nuclear Magnetic Resonance; Oseltamivir; PTPN11 gene; Pharmaceutical Preparations; Positioning Attribute; Process; Property; Proteins; RNA Binding; RNA Recognition Motif; Reporting; Resistance; Rimantadine; Screening procedure; Structure; Testing; Texas; Universities; Validation; Variant; Vietnam; Viral; Virus; Virus Replication; X-Ray Crystallography; austin; base; design; drug development; high throughput screening; improved; influenzavirus; inhibitor/antagonist; mRNA Cleavage and Polyadenylation Factors; mortality; pandemic disease; research study; structural biology; three dimensional structure; viral resistance; virology; virtual

DESCRIPTION (provided by applicant): Influenza A and B viruses cause a highly contagious respiratory disease in humans. Influenza A viruses, which have been isolated from a wide variety of avian and mammalian species, are responsible for pandemics that have caused high mortality rates. Avian H5N1 influenza A viruses, which have spread from Asia to Europe and Africa, are prime candidates for causing the next pandemic. The current antivirals against influenza A virus target either the M2 ion channel protein (amantadine/rimantadine) or the neuraminidase (NA) (oseltamivir/zamanivir). Many of the human isolates of H5N1 viruses are already resistant to amantadine, and H5N1 viruses that are partially, or completely, resistant to oseltamivir have recently been reported, highlighting the need for new antivirals. Our goal is to target a different, highly conserved influenza A virus-encoded protein, the NS1 protein, for drug development. The NS1 protein of influenza A virus will be designated as the NS1A protein to distinguish it from the NS1 protein encoded by influenza B virus, which will be designated as the NS1B protein. Influenza B viruses appear to infect only humans: We will target two functions of the NS1A protein that are crucial for virus replication: (1) double- stranded RNA (dsRNA)-binding by its N-terminal RNA-binding domain; and (2) binding by its effector domain of a cellular protein required for the 3' end processing of cellular pre-mRNAs (the 30-kDa subunit of the cleavage and polyadenylation factor, or CPSF30). The NS1B protein also has a dsRNA-binding function that we will target. We have already obtained strong evidence that these NS1 binding sites are valid new targets for drug development and have identified key features of their three-dimensional structure by X-ray crystallography and nuclear magnetic resonance (NMR) methods. We will now proceed to identify, assay and develop small organic ligand inhibitors for these three NS1 domains. This project is based on a strong and ongoing collaboration between virology efforts in the Krug laboratory at the University of Texas at Austin (UT-Austin) and structural biology efforts in the Montelione laboratory at Rutgers University. This effort will be augmented by the participation of Drs. Robertus, Ellington and Anslyn at UT-Austin and by the facilities of the Texas Institute for Drug and Diagnostics Development. In addition, the Paessler laboratory at the University of Texas Medical Branch will carry out animal experiments to test our inhibitory compounds.

描述（由申请人提供）：甲型和乙型流感病毒在人类中引起高度传染性呼吸道疾病。甲型流感病毒是从多种鸟类和哺乳动物中分离出来的，它是导致高死亡率的流行病的罪魁祸首。禽 H5N1 甲型流感病毒已从亚洲传播到欧洲和非洲，是引发下一次大流行的主要候选病毒。目前针对甲型流感病毒的抗病毒药物靶向 M2 离子通道蛋白（金刚烷胺/金刚乙胺）或神经氨酸酶 (NA)（奥司他韦/扎马尼韦）。许多人类分离的 H5N1 病毒已经对金刚烷胺产生耐药性，最近还报道了对奥司他韦部分或完全耐药的 H5N1 病毒，这凸显了对新型抗病毒药物的需求。我们的目标是针对一种不同的、高度保守的甲型流感病毒编码蛋白 NS1 蛋白进行药物开发。甲型流感病毒的NS1蛋白将被指定为NS1A蛋白，以区别于乙型流感病毒编码的NS1蛋白，后者将被指定为NS1B蛋白。 B 型流感病毒似乎只感染人类：我们将针对 NS1A 蛋白的两个对病毒复制至关重要的功能：（1）通过其 N 端 RNA 结合结构域进行双链 RNA (dsRNA) 结合； (2) 通过其效应结构域与细胞前 mRNA（切割和聚腺苷酸化因子的 30-kDa 亚基，或 CPSF30）的 3' 末端加工所需的细胞蛋白结合。 NS1B 蛋白还具有我们将瞄准的 dsRNA 结合功能。我们已经获得强有力的证据表明这些 NS1 结合位点是药物开发的有效新靶点，并通过 X 射线晶体学和核磁共振 (NMR) 方法鉴定了其三维结构的关键特征。我们现在将继续鉴定、分析和开发这三个 NS1 结构域的小型有机配体抑制剂。该项目基于德克萨斯大学奥斯汀分校 (UT-Austin) 的 Krug 实验室的病毒学工作和罗格斯大学的 Montelione 实验室的结构生物学工作之间的强有力且持续的合作。这项努力将因博士的参与而得到加强。 Robertus、Ellington 和 Anslyn 在 UT-Austin 以及德克萨斯药物和诊断开发研究所的设施旁进行。此外，德克萨斯大学医学分校的Paessler实验室将进行动物实验来测试我们的抑制化合物。