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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.

项目总结世界正沉浸在一场仅次于1918-1919年西班牙流感大流行的健康危机中。区别在于在今天的危机和一个世纪前的危机之间，我们拥有先进的通信技术以便全球各地的大量人口意识到风险并采取适当的措施预防措施，如使用隔离、隔离、社交距离、口罩和洗手。政府已经关闭了学校，并宣布大型社交集会为非法。医疗服务有了很大的改善，而受影响最严重的人在新冠肺炎无法治愈的情况下接受了对症治疗。这个必须在多个方面处理问题，如疫苗开发、药物开发和新技术，减轻病毒影响的化验。拟议的项目意义重大，因为它提出了一种新颖的 SARS-CoV-2中一种独特但尚未开发的RNA结构的体外生物物理筛选病毒，将来可以用来产生RNA特异性的抗病毒化合物。核酸是药物设计的很有前途的途径，既是治疗药物，也是靶点。在这里，我们提出一种用于识别一类新的RNA特异性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成分，我们建议一种生物物理筛选试验是鉴定这类配体的第一步。第一，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、表征并用于鉴定一种RNA特异性荧光探针。然后，优化后的探头将用于开发高通量的发现与该RNA的纳米分子结合的筛选试验。然后，RNA特异的高亲和力结合物将与序列特异的RNA结合配体结合，以验证该方法的发展及其实用性。这个作用机制将通过抑制萤火虫荧光素酶的翻译在报告基因测试中得到证实 (具体目标2)。虽然这个应用程序的重点，作为必要的第一步，是在开发和对SARS-CoV-2潜在RNA结构的生物物理测试的验证，成功地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是唯一有资格执行这些任务的除了为科学界提供模板外，还在第二阶段分析和开发潜在的线索将筛选技术用于他们自己的发现平台。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病毒的其他RNA结构，并提供筛选资源，为科学界提供服务。