SARS Receptor Characterization/Virus Binding Blockagage

围绕引起严重急性呼吸系统综合症（SARS）的病毒颗粒的“冠状”是其中一种 冠状病毒的特征，一组大的，包膜RNA病毒，引起重要的呼吸道和肠道 人类、家畜和家禽的疾病。冠由大的病毒刺突（S）糖蛋白组成， 确定病毒的宿主范围和组织嗜性，影响病毒毒力，并作为抗病毒的潜在靶点 疫苗和药物。在项目1中，我们将研究冠状病毒S糖蛋白的结构和功能 导致SARS（SARS-CoV）。我们将首先鉴定易受感染的人类细胞系和组织， 然后分离宿主细胞大分子，可能是一种蛋白质，SARS-CoV的S蛋白用作 受体启动感染。我们将确定是否针对刺突或受体蛋白和/或小的抗体， 模拟刺突或受体的分子可以阻止SARS-CoV对细胞的感染。我们会把它们作为铅 用于开发治疗或预防SARS的新药或疫苗的化合物。S蛋白后， 当病毒粒子与宿主细胞膜上的受体结合时，刺突经历一系列程序化的构象变化， 导致膜融合和病毒感染的变化。我们将描述这些变化并开发抗体 或阻断病毒与受体结合以及SARS-CoV与细胞膜融合的药物， 治疗或预防SARS的药物。项目3和项目4将研究S蛋白的结构和功能 及其受体，并将该受体与动物的同源分子进行比较（项目2）以发现 SARS-CoV感染的种属特异性和组织嗜性的分子基础。我们将提供cDNA克隆 我们的同事在项目5和6中，谁将表达人类受体在转基因小鼠， 发展小型动物模型，以研究严重急性呼吸系统综合症的发病机制及评估候选药物和疫苗 对抗SARS

The "corona" surrounding the virus particles that cause Severe Acute Respiratory Syndrome (SARS) is one of the hallmarks of coronaviruses, a group of large, enveloped RNA viruses that cause important respiratory and enteric diseases of humans, domestic animals and poultry. The corona is composed of large viral spike (S) glycoproteins that determine the host range and tissue tropism of the virus, affect virus virulence and serve as potential targets for antiviral vaccines and drugs. In Project 1, we will study the structure and functions of the S glycoprotein of the coronavirus that causes SARS (SARS-CoV). We will first identify human cell lines and tissues that are susceptible to infection with SARS-CoV, and then isolate a host cell macromolecule, probably a protein, that the S protein of SARS-CoV uses as a receptor to initiate infection. We will determine whether antibodies against the spike or receptor protein and/or small molecules that mimic the spike or receptor can block infection of cells by SARS-CoV. We will evaluate them as lead compounds for development of novel drugs or vaccines for treatment or prevention of SARS. After S proteins on virions bind to the receptor on the host cell membrane, the spikes undergo a programmed series of conformational changes that lead to membrane fusion and virus infection. We will characterize these changes and develop antibodies or drugs that block virus binding to receptors and fusion of SARS-CoV with cellular membranes as additional novel drugs for treating or preventing SARS. With Projects 3 and 4 we will study the structures and functions of S protein and its receptor, and compare the receptor with homologous molecules from animals (Project 2) to discover the molecular basis for the species specificity and tissue tropism of SARS-CoV infection. We will provide cDNA clones encoding the receptor to our colleagues in Projects 5 and 6, who will express the human receptor in transgenic mice to develop small animal models for studies on SARS pathogenesis and for evaluation of candidate drugs and vaccines against SARS.