Fusion Inhibitors of H5N1

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。这个 流感病毒血凝素(HA)是一个有吸引力的药物靶标，因为它们是病毒进入所必需的，以及 对于病毒复制是必不可少的。我们假设目前正在研发的融合抑制剂 该计划将有效地对抗不同的病毒株，特别是HPAI病毒。进一步发展的具体目标 这些抑制剂是：目标1.确定对不同H5N1流感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具有单一EC50值的先导化合物 不同流感病毒株之间的数字纳米分子，包括H5N3(疫苗株)、H3N1、H1N1和 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Lead开发一个类比资料库。我们建议测量抑制作用 候选化合物对不同H5N1流感病毒株的效力。先导化合物 从这些研究中确定的结果将作为计划10的一部分推进到临床前研究。 确定HA蛋白抑制剂的作用机制。我们的初步数据表明，融合 我们开发的抑制剂可以改变HA的结构。对于目标1中确定的有效化合物 对于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部位图，我们将HA蛋白与结合的抑制剂共结晶， 我们还将产生并鉴定抗药性变异体。重组HA将用不同的方法治疗 为了绘制构象敏感区域的图谱，我们使用了一系列的蛋白水解酶。目标3.确定药物组合是否 包括HA抑制剂在预防疾病方面比现有单一药物疗法更具优势 并避免抗药性。HA抑制剂的广泛使用可能导致抗药性的出现 病毒，与已观察到的神经氨酸酶(NA)获得抗药性类似 和M2抑制剂。我们假设HA抑制剂与现有的NA和/或M2结合使用 抑制剂将有助于中和耐药性，降低传染病的严重程度。

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.