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: 10223018
• 负责人: Sara Cherry
• 金额: $ 33.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-18 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223018
• 关键词: 2019-nCoV; A549; Adjuvant; Agonist; Animal Model; Antibodies; Antiviral Agents; Biological Assay; Bunyaviridae; COVID-19; Cells; China; Chloroquine; Clinical Trials; Coronavirus; Development; Disease Outbreaks; Dose; Double-Stranded RNA; Drug Screening; Engineering; Epithelial Cells; FDA approved; Filovirus; Flavivirus; Funding; Future; Goals; Grant; Hand; Hour; Human; Immune; Infection; Libraries; Methods; Microscopy; Monitor; Nuclear; Pharmaceutical Preparations; Positioning Attribute; Proteins; Publishing; Reproducibility; Running; Stains; Testing; Therapeutic; Therapeutic Uses; Time; Vaccines; Virus; Virus Diseases; Virus Inhibitors; Work; Zika Virus; base; cytotoxicity; drug testing; experience; high throughput screening; indexing; inhibitor/antagonist; novel; novel therapeutics; parent grant; pathogen; patient population; receptor; remdesivir; response; screening; small molecule

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.

总结