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A biophysical assay targeting SARS CoV-2 RNA

针对 SARS CoV-2 RNA 的生物物理检测

基本信息

批准号：
10653818
负责人：
sandra Paige story
金额：
$ 29.87万
依托单位：
NUBAD, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-27 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653818
关键词：
1918 influenza pandemic 2019-nCoV 5&apos Untranslated Regions Address Affect Affinity Amino Sugars Antisense Oligonucleotides Antiviral Agents Awareness Bacterial Genes Binding Biological Assay Biophysics COVID-19 COVID-19 pandemic COVID-19 treatment Caring Cell Culture Techniques Cessation of life Chemicals Chemistry Communication Communities Complex Coughing Country Development Disease Drug Design Elements Employment Event Exposure to Firefly Luciferases Fluorescence Fluorescent Probes Future Genes Genetic Transcription Genome Government Grant Handwashing Health Health Status Healthcare Systems High Pressure Liquid Chromatography Human In Vitro Individual Infection Infection prevention Interruption Laboratories Lead Legal patent Libraries Life Ligand Binding Ligands Masks Medical Mental Health Messenger RNA Modeling National Institute of Allergy and Infectious Disease Nucleic Acids Persons Phase Population Proteins Proteome Public Health Qualifying Quarantine RNA RNA Binding RNA Sequences RNA Viruses RNA library RNA replication Rapid screening Reporter Genes Resources Respiratory distress Reverse Transcription Ribonucleic Acid Regulatory Sequences Risk Role SARS coronavirus SARS-CoV-2 infection Scientist Services Severe Acute Respiratory Syndrome Small Business Innovation Research Grant Small Business Technology Transfer Research Social Distance Solid Structure Technology Tennessee Therapeutic Transactivation Transcript Translations Universities Untranslated Regions Vaccination Vaccines Validation Viral Viral Proteins Virus Virus Replication Work analog assay development biophysical analysis chemical synthesis combat coronavirus pandemic design drug development experimental study genomic RNA high throughput screening improved innovation interest microbial mutant nanomolar new technology novel pandemic disease phase 2 study phosphorodiamidate morpholino oligomer physical conditioning prevent respiratory school closure screening social stem success symptom management symptom treatment technology development vaccine development viral RNA

项目摘要

PROJECT SUMMARY The world is immersed in a health crisis rivaled only by the Spanish flu pandemic of 1918-1919. The difference between the crisis of today and the crisis a century ago is that we have advanced communication technology greatly so that huge populations of people around the globe are aware of risks and can take appropriate precautions, such as the employment of quarantining, isolation, social distancing, and masks and handwashing. Governments have closed schools and outlawed large social gatherings. Medical care has greatly improved, and those most affected have received symptomatic treatment in the absence of a cure for CoVID-19. The problem must be dealt at multiple fronts, such as vaccine development, drug development and new technologies, assays for mitigating viral effects. The proposed project is significant because it proposes a novel in vitro biophysical screening assay for a unique and yet untapped RNA structure in SARS-CoV-2 virus, that can be used in the future to generate RNA specific antiviral compounds. Nucleic acids are promising avenues for drug design, both as therapeutics and as targets. Here we propose an innovative screening approach for identification of a novel class of ligands that are specific for an RNA element within the viral RNA genome that is vital for replication of the virus, and we propose a biophysical screening assay as a first step for identifying such ligands. First, as outlined in Specific Aim 1, we will characterize a model nucleic acid (RNA) domain that will be synthesized, characterized and used to identify a RNA specific fluorescent probe. The optimized probe will then be used for developing a high-throughput screening assay for discovery of nanomolar binders to this RNA. The RNA specific high-affinity binders will then be combined with sequence-specific RNA binding ligands to validate the assay development and its utility. The mechanism of action will be confirmed using inhibition of firefly luciferase translation in a reporter gene assay (Specific Aim 2). While the focus of this application, as the needed first step, is on the development and validation of the biophysical assay for the underlying SARS-CoV-2 RNA structures, a successful validation of the approach will open the doors for discovery and development of lead compounds for inhibition of SARS-CoV in Phase II studies. NUBAD and its team of scientists and collaborators is uniquely qualified to perform these assays and develop the potential leads in Phase II, in addition to providing a template for the scientific community to use the screening technology for their own discovery platforms. Success of the approach will also allow us to expand the screening technology to other RNA structures in SARS and other RNA viruses, and provide the screening resource as a service to the scientific community.

项目概要世界正陷入一场健康危机，其规模仅次于 1918 年至 1919 年的西班牙流感大流行。区别今天的危机和一个世纪前的危机之间的区别在于我们拥有先进的通讯技术从而使全球大量人口意识到风险并采取适当的措施预防措施，例如隔离、隔离、社交距离、戴口罩和洗手。政府关闭了学校并禁止大型社交聚会。医疗条件大大改善，受影响最严重的人在 CoVID-19 尚无治愈方法的情况下接受了对症治疗。这必须从多个方面解决问题，例如疫苗开发、药物开发和新技术，减轻病毒影响的测定。拟议的项目意义重大，因为它提出了一种新颖的 SARS-CoV-2 中独特且尚未开发的 RNA 结构的体外生物物理筛选试验病毒，未来可用于生成 RNA 特异性抗病毒化合物。核酸是药物设计的有前途的途径，无论是作为治疗药物还是作为靶标。在这里我们提出一个用于鉴定特定于 RNA 的新型配体的创新筛选方法病毒RNA基因组中对病毒复制至关重要的元件，我们提出了一个生物物理筛选测定是鉴定此类配体的第一步。首先，如具体目标中所述 1，我们将表征一个模型核酸 (RNA) 结构域，该结构域将被合成、表征并用于识别 RNA 特异性荧光探针。然后，优化后的探针将用于开发高通量用于发现该 RNA 的纳摩尔结合物的筛选测定。然后，RNA 特异性高亲和力结合物将与序列特异性 RNA 结合配体结合以验证检测开发及其实用性。这通过在报告基因测定中抑制萤火虫荧光素酶翻译来确认作用机制（具体目标 2）。虽然作为所需的第一步，该应用程序的重点是开发和对潜在 SARS-CoV-2 RNA 结构的生物物理测定进行验证，成功验证了该方法将为发现和开发抑制 SARS-CoV 的先导化合物打开大门在第二阶段研究中。 NUBAD 及其科学家和合作者团队具有执行这些任务的独特资格除了为科学界提供模板外，还可以在第二阶段进行分析并开发潜在的先导化合物将筛选技术用于自己的发现平台。该方法的成功还将使我们能够将筛选技术扩展到SARS和其他RNA病毒中的其他RNA结构，并提供筛选资源作为对科学界的服务。