Small Molecule Screening to Identify Novel Sars-CoV-2 Therapeutics

通过小分子筛选鉴定新型 Sars-CoV-2 疗法

基本信息

批准号：
10239297
负责人：
Sara Cherry
金额：
$ 22.48万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239297
关键词：
Address Agonist Antigens Antiviral Agents Antiviral Response Arbovirus Infections Autophagocytosis Biochemical Biological COVID-19 therapeutics Cell Death Cells Cellular biology Data Drosophila genus Encephalitis Exhibits Genetic Polymorphism Genetic Transcription Goals Human Immune response Immunity Infection Infection Control Innate Immune Response Innate Immune System Insect Vectors Insecta Intervention Invaded Knowledge La Crosse virus Ligands Link Mammalian Cell Mammals Molecular Natural Immunity Nature Neuraxis Neuroglia Neurons Orthobunyavirus Outcome Output Pathogenesis Pathway interactions Pattern Recognition Pattern recognition receptor Pharmacology Receptor Signaling Research Rift Valley fever virus Role Shapes Signal Pathway Signal Transduction System TLR2 gene Therapeutic Tissues Tropism Vaccines Virus Virus Diseases antiviral immunity arthropod-borne beta-Glucans cell type combat dectin 1 dimer human disease insight novel novel strategies pathogen pathogenic virus programs receptor response screening small molecule tissue tropism treatment strategy

项目摘要

Summary The current outbreak of the coronavirus in China (SARS-CoV-2) has spread rapidly. There are experimental drugs which will be tested; however, there are no approved therapeutics or vaccines. Indeed, there are tests underway to determine whether remdesivir, which was developed against filoviruses, can be repurposed against SARS-CoV-2 infection. It would be transformative if we could identify additional small molecules that could be repurposed to treat the outbreak of SARS-CoV-2 infection. Given that the goal of the parent grant (R01AI150246) is to discover antivirals active against bunyaviruses, based on findings from cell based screening, and that we have broad expertise in diverse viruses, we are applying for Supplemental funding (notice number NOT-AI-20-030, PA-18-035) to expand the scope of the existing grant to use the same methods (small molecule screening) to identify antiviral therapeutics active against SARS-CoV-2 infection. We will screen two libraries of known bioactives to potentially repurpose existing therapeutics. First, we will test a library of innate immune agonists (~100 PAMPs) for their ability to block SARS-CoV-2 infection in human cells including airway cells. Second, we will screen another ‘actionable’ library that I have created as the Director of the High-throughput Screening core at UPENN. We created a library of ~3000 drugs that includes ~1500 FDA approved compounds, ~1000 drugs in clinical trials and the remaining drugs have known targets. This library has been used for repurposing (as is being done with the Gilead drug remdesivir that was originally developed against filoviruses) to more rapidly identify active therapeutics for future testing in humans. We will also determine if any of our active antivirals act synergistically with remdesivir since this drug is currently under development for use against COVID-19. We expect to identify additional drugs with activity against SARS-CoV-2.

概括目前中国爆发的冠状病毒（SARS-CoV-2）传播迅速，有实验药物。将进行测试；然而，目前还没有批准的治疗方法或疫苗。事实上，正在进行测试。确定针对丝状病毒开发的瑞德西韦是否可以重新用于对抗 SARS-CoV-2 如果我们能够找到其他可以重新用于治疗感染的小分子，那将是革命性的。鉴于家长资助 (R01AI150246) 的目标是发现 SARS-CoV-2 感染的爆发。根据细胞筛选的结果，我们有广泛的抗布尼亚病毒抗病毒药物由于我们在多种病毒方面拥有丰富的专业知识，我们正在申请补充资金（通知编号 NOT-AI-20-030、PA-18-035）扩大现有拨款的范围，使用相同的方法（小分子筛选）来识别抗病毒药物我们将筛选两个已知的潜在生物活性物质库。首先，我们将测试先天免疫激动剂库（约 100 个 PAMP）的能力。阻止包括气道细胞在内的人类细胞中的 SARS-CoV-2 感染其次，我们将筛选另一种“可操作的”。我作为 UPENN 高通量筛选核心主任创建的库我们创建了一个库。约 3000 种药物，其中包括约 1500 种 FDA 批准的化合物、约 1000 种处于临床试验的药物以及其余药物该库已用于重新利用（正如吉利德药物瑞德西韦所做的那样）最初是针对丝状病毒开发的），以更快地识别活性疗法，用于未来的测试我们还将确定我们的任何活性抗病毒药物是否与瑞德西韦具有协同作用，因为该药物是目前正在开发用于对抗 COVID-19 的药物，我们预计会发现其他具有对抗活性的药物。 SARS-CoV-2。