SARS Coronavirus: Inhibition of Entry

描述（申请人提供）：从2002年11月到2003年6月的7个月时间里，突发性急性呼吸系统综合症（SARS）疫情已蔓延到30个国家，造成800多人死亡。这一流行病是一个重大的公共卫生紧急事件，它导致医院和学校关闭，并造成人员伤亡、旅行不便和严重的经济损失。现时并没有有效的药物或疫苗可治疗或预防沙士。人们对新出现的冠状病毒（SARS-CoV）知之甚少，这种冠状病毒显然是从野生动物跳到人类身上的，现在正在人与人之间传播。该项目的6名主要研究人员计划对SARS冠状病毒包膜上的刺突（S）糖蛋白进行协调分析，以了解病毒可能感染哪些物种，研究S蛋白如何作为允许病毒进入宿主细胞的分子关键，并开发新的抗病毒药物和疫苗来对抗SARS冠状病毒。第一个目标是确定病毒的细胞受体，了解它如何启动病毒感染，并开发抗体和候选抗病毒药物，阻止病毒感染人类细胞。霍姆斯博士曾深入研究过其他人类和动物冠状病毒的受体，是该计划项目赠款和项目1的首席研究员。DeMartini博士（项目2）研究了病毒如何导致动物肺部疾病。他将鉴定易受SARS冠状病毒感染的动物，并研究SARS肺部病理学。Hodges博士（项目3）和Wang博士（项目4）将与Holmes博士（项目1）一起使用生物物理，生物化学和功能测定研究病毒刺突蛋白，并通过X射线晶体学了解蛋白质的哪些部分与受体结合，抗体靶向刺突的位置以及刺突如何引起膜融合。温特沃斯博士（项目5）和梅森博士（项目6）将开发表达SARS冠状病毒人类受体的转基因小鼠，并利用它们来了解SARS冠状病毒如何致病。Shallow先生（行政核心A）将协调将在5个机构完成的项目的管理，Holmes博士将协调项目之间的科学互动。Pearson博士（病毒核心B）将与所有其他项目的研究人员合作，在生物安全3级实验室研究传染性SARS-CoV。Gill博士（蛋白质核心C）将指导病毒刺突蛋白，受体蛋白和抗体的合成和纯化，这些蛋白和抗体对每个项目都至关重要。这项研究将有助于解释SARS冠状病毒的起源，解释SARS的病理学，开发针对SARS的候选疫苗和药物，并在新的SARS动物模型中进行测试。

DESCRIPTION (provided by applicant): The Sudden Acute Respiratory Syndrome (SARS) epidemic has spread to 30 countries and killed more than 800 people in the 7-month period from November 2002, to June 2003. The epidemic is a major public health emergency that has closed hospitals and schools and caused quarantines, travel advisories, and severe economic losses. No drugs or vaccines with proven efficacy are available to treat or prevent SARS. Little is known about the new, emerging coronavirus (SARS-CoV) that apparently jumped from wild animals into humans, and is now transmitted from person to person. The 6 principal investigators on this Program Project Grant have planned a coordinated analysis of the spike (S) glycoprotein on the envelope of the SARS-coronavirus to learn what species the virus can potentially infect, study how the S protein works as a molecular key to allow the virus to enter host cells, and develop new anti-viral drugs and vaccines to combat SARS-CoV. The first goals are to identify the cellular receptor for the virus, learn how it initiates virus infection, and develop antibodies and candidate anti-viral drugs that block virus infection of human cells. Dr. Holmes, who has studied receptors for other human and animal coronaviruses intensively, is the principal investigator of this Program Project Grant and Project 1. Dr. DeMartini (Project 2) has studied how viruses cause diseases of the lung in animals. He will identify animals susceptible to SARS-CoV infection, and study SARS lung pathology. Dr. Hodges (Project 3) and Dr. Wang (Project 4) will study the viral spike protein using biophysical, biochemical and functional assays with Dr. Holmes (Project 1), and by X-ray crystallography to learn what parts of the protein bind to the receptor, where antibodies target the spike, and how the spike causes membrane fusion. Dr. Wentworth (Project 5) and Dr. Mason (Project 6) will develop transgenic mice that express the human receptor for SARS-CoV and use them to learn how SARS-CoV causes disease. Mr. Shallow, (Administrative Core A) will coordinate the administration of the Projects that will be done in 5 institutions, and Dr. Holmes will coordinate the scientific interactions between the Projects. Dr. Pearson (Virus Core B) will work with the infectious SARS-CoV in the Biosafety Level 3 lab in collaboration with investigators from all of the other projects. Dr Gill (Protein Core C) will direct the synthesis and purification of viral spike proteins, receptor proteins and antibodies that are essential for each of these projects. This research will help to explain the origin of SARS-CoV, explain the pathology of SARS, develop candidate vaccines and drugs against SARS, and test them in new animal models for SARS.