Fusion Inhibitors of H5N1

H5N1 融合抑制剂

• 批准号: 8375867
• 负责人: MING LUO
• 金额: $ 32.98万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8375867
• 关键词: Africa; Amantadine; Asia; Avian Influenza A Virus; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Clinical Research; Combined Modality Therapy; Communicable Diseases; Data; Development; Digit structure; Disease; Domestic Fowls; Drug Combinations; Drug Delivery Systems; Drug resistance; Europe; Funding; Health; Hemagglutinin; Human; In Vitro; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Lead; Libraries; Maps; Measures; Membrane Fusion; Neuraminidase; Neuraminidase inhibitor; Oseltamivir; Peptide Hydrolases; Pharmaceutical Preparations; Population; Process; Protein Conformation; Proteins; Recombinants; Reporting; Resistance; Resistance development; Severities; Severity of illness; Structure; Vaccines; Variant; Viral; Virus; Virus Replication; analog; base; biodefense; design; drug resistant virus; in vivo; influenza virus strain; influenzavirus; inhibitor/antagonist; insight; ion channel blocker; mortality; pandemic disease; pre-clinical; preclinical study; programs; wild bird

Emerging avian influenza viruses pose an increasing threat to domestic poultry and human health. The influenza virus hemagglutinin (HA) is an attractive drug target because they are essential for viral entry, and indispensable for virus replication. We hypothesize that fusion inhibitors currently under development in this program will be potent against diverse virus strains, especially HPAI viruses. Specific aims to further develop these inhibitors are:Aim 1. Identify fusion inhibitors that are potent against diverse strains of H5N1 influenza viruses. Our preliminary studies have identified a group of lead compounds that have EC50 values in single digit nanomoles across diverse influenza virus strains including H5N3 (vaccine strain), H3N2, H1N1 and type B. To identify potential candidates for preclinical and eventual clinical studies against HPAI H5N1 viruses, we propose to develop a library of analogs based on the initial lead. We propose to measure the inhibitory potencies of candidate compounds against diverse strains of H5N1 influenza viruses. Lead compounds identified from these studies will be advanced to preclinical studies as a component of Program 10. Aim 2. Determine the mechanisms of action of HA protein inhibitors.Our preliminary data indicate that the fusion nhibitors we have developed alter the structure of HA. For compounds identified in Aim 1 that are potent against H5N1 viruses, we will determine which step of virus entry is blocked using biological and biochemical assays. To map the binding sites of compounds, we will co-crystallize the HA protein with bound inhibitor, and we will also generate and characterize resistant variants. Recombinant HA will be treated with different proteases in order to map the conformationally sensitive regions. Aim 3. Determine if drug combinations that nclude HA inhibitors provide advantages over existing single-agent therapies in protecting against disease and avoiding drug resistance. A widespread use of HA inhibitors could result in the emergence of drugesistant viruses, similar to the acquisition of drug resistance that has been observed for neuraminidase (NA) and M2 inhibitors. We hypothesize that the use of HA inhibitors in combination with existing NA and/or M2 nhibitors will help counteract drug resistance and decrease the severity of infectious disease.

新出现的禽流感病毒对家禽和人类健康构成越来越大的威胁。这 流感病毒血凝素（HA）是一个有吸引力的药物靶点，因为它们对于病毒进入至关重要，并且 病毒复制所必需的。我们假设目前正在开发融合抑制剂 该程序将有效对抗多种病毒株，尤其是高致病性禽流感病毒。进一步发展的具体目标 这些抑制剂是：目标 1. 鉴定对多种 H5N1 流感病毒株有效的融合抑制剂 病毒。我们的初步研究已经确定了一组在单一化合物中具有 EC50 值的先导化合物。 不同流感病毒株的数字纳摩尔，包括 H5N3（疫苗株）、H3N2、H1N1 和型 B. 为了确定针对 HPAI H5N1 病毒的临床前和最终临床研究的潜在候选者，我们 建议根据最初的先导开发一个类似物库。我们建议测量抑制 候选化合物对抗不同 H5N1 流感病毒株的效力。铅化合物 从这些研究中确定的结果将被推进到临床前研究，作为计划 10 目标 2 的一部分。 确定HA蛋白抑制剂的作用机制。我们的初步数据表明融合 我们开发的抑制剂会改变 HA 的结构。对于目标 1 中确定的有效化合物 针对H5N1病毒，我们将通过生物和生化来确定病毒进入的哪一步被阻断 化验。为了绘制化合物的结合位点图谱，我们将 HA 蛋白与结合的抑制剂共结晶， 我们还将生成并鉴定耐药变体。重组HA将采用不同的处理方法 蛋白酶以绘制构象敏感区域。目标 3. 确定药物组合是否 与现有单药疗法相比，包含 HA 抑制剂在预防疾病方面具有优势 并避免产生耐药性。 HA抑制剂的广泛使用可能导致耐药性的出现 病毒，类似于在神经氨酸酶 (NA) 中观察到的耐药性的获得 和M2抑制剂。我们假设 HA 抑制剂与现有的 NA 和/或 M2 组合使用 抑制剂将有助于对抗耐药性并降低传染病的严重程度。