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

• 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
• 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

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.

摘要 目前在中国暴发的冠状病毒(SARS-CoV-2)传播迅速。有实验药物 这将进行测试；然而，还没有批准的疗法或疫苗。事实上，目前正在进行测试，以 确定针对丝状病毒开发的雷米希韦是否可以用于治疗SARS-CoV-2 感染。如果我们能识别出更多可以被重新利用来治疗的小分子，那将是革命性的。 SARS-CoV-2感染的暴发。鉴于父拨款(R01AI150246)的目标是发现 根据基于细胞的筛查结果，抗病毒药物对布尼亚病毒有效，我们有广泛的 在多种病毒方面的专业知识，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)识别抗病毒药物 积极对抗SARS-CoV-2感染的治疗药物。我们将筛选两个已知生物活性物质文库，以潜在地 改变现有疗法的用途。首先，我们将测试先天免疫激动剂(约100个PAMP)的能力 阻断SARS-CoV-2在包括呼吸道细胞在内的人类细胞中的感染。第二，我们将放映另一部《可行的》 我作为宾夕法尼亚大学高通量筛选中心主任创建的图书馆。我们创建了一个图书馆 ~3000种药物，其中包括~1500种FDA批准的化合物，约1000种临床试验药物和剩余药物 有已知的目标。这个库已被用于重新用途(就像对基列德药物redesivir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，以便将来在 人类。我们还将确定我们的任何活性抗病毒药物是否与雷米西韦有协同作用，因为该药物 目前正在开发中，用于对抗新冠肺炎。我们预计将确定更多具有抗肿瘤活性的药物 SARS-CoV-2。