SARS Receptor Characterization/Virus Binding Blockagage

SARS 受体表征/病毒结合阻断

基本信息

批准号：
7952803
负责人：
Kathryn V Holmes
金额：
$ 16.66万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-24 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7952803
关键词：
Affect Amino Acids Animal Model Animals Antibodies Antiviral Agents Binding Binding Sites Carbohydrates Cell membrane Cells Cellular Membrane Complementary DNA Complex Coronavirus Coronavirus Infections Development Domestic Animals Domestic Fowls Enteral Essential Amino Acids Evaluation Genetic Recombination Glycoproteins Homologous Gene Human Human Cell Line Human Virus Infection Laboratories Lead Maps Membrane Membrane Fusion Molecular Mus Mutation Pathogenesis Peptides Pharmaceutical Preparations Prevention Proteins RNA RNA Viruses Recombinants Resistance Retroviridae Risk Series Severe Acute Respiratory Syndrome Species Specificity Specificity Structure Testing Time Tissues Transgenic Mice Vaccines Variant Viral Viral Proteins Virion Virulence Virus Virus Diseases Virus Receptors X-Ray Crystallography base cDNA Library coronavirus receptor drug candidate human disease macromolecule mutant novel pandemic disease prevent programs protein structure protein structure function receptor receptor binding respiratory small molecule tissue tropism

项目摘要

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.

引起严重急性呼吸综合征（SARS）的病毒颗粒周围的“电晕”是其中之一冠状病毒的标志，一组引起重要呼吸系统的大型包裹的RNA病毒人类，家畜和家禽的疾病。电晕由大型病毒尖峰（S）糖蛋白组成确定病毒的宿主范围和组织偏向主义，影响病毒毒力，并作为抗病毒药物的潜在靶标疫苗和药物。在项目1中，我们将研究冠状病毒S糖蛋白的结构和功能这会导致SARS（SARS-COV）。我们将首先确定容易感染的人类细胞系和组织 SARS-COV，然后隔离宿主细胞大分子，可能是一种蛋白质，SARS-COV的S蛋白用作A 引发感染的受体。我们将确定针对尖峰或受体蛋白和/或小的抗体是模拟尖峰或受体的分子可以通过SARS-COV阻断细胞的感染。我们将评估它们作为铅用于开发新药物或疫苗治疗或预防SARS的化合物。 S蛋白上的S蛋白病毒体与宿主细胞膜上的受体结合，尖峰经历了一系列编程的构象导致膜融合和病毒感染的变化。我们将表征这些变化并发展抗体或阻断病毒与受体结合的药物，并将SARS-COV与细胞膜融合为附加的新型药物用于治疗或预防SAR的药物。通过项目3和4，我们将研究S蛋白的结构和功能及其受体，并将受体与动物的同源分子进行比较（项目2），以发现 SARS-COV感染的物种特异性和组织偏向主义的分子基础。我们将提供cDNA克隆在项目5和6中，将受体编码为我们的同事，他们将在转基因小鼠中表达人类受体开发小动物模型，用于研究SARS发病机理和评估候选药物和疫苗反对Sars。