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

总结 目前在中国爆发的冠状病毒（SARS-CoV-2）迅速蔓延。有实验性药物 这将是测试;然而，没有批准的治疗或疫苗。事实上，目前正在进行测试， 确定是否可以将针对丝状病毒开发的瑞德西韦重新用于SARS-CoV-2 感染如果我们能够识别出更多的小分子， SARS-CoV-2感染的爆发。鉴于母基金（R 01 AI 150246）的目标是发现 抗布尼亚病毒活性，基于基于细胞筛选的结果，我们有广泛的 由于我们在不同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） 扩大现有资助的范围，以使用相同的方法（小分子筛选）来识别抗病毒药物 抗SARS-CoV-2感染的有效治疗剂。我们将筛选两个已知生物活性物质库， 重新利用现有的治疗方法。首先，我们将测试一个先天免疫激动剂库（约100种PAMP）的能力， 以阻断SARS-CoV-2在包括气道细胞在内的人体细胞中的感染。其次，我们将筛选另一个'可操作' 我作为宾夕法尼亚大学高通量筛选核心的主任创建了这个库。我们建立了一个图书馆， 约3000种药物，包括约1500种FDA批准的化合物，约1000种临床试验药物和其余药物 有已知的目标。这个库已经被用于再利用（就像吉利德药物remdesivir所做的那样 最初是针对丝状病毒开发的），以更快地鉴定活性治疗剂，用于未来的测试， 人类我们还将确定我们的任何活性抗病毒药物是否与remdesivir协同作用，因为这种药物是 目前正在开发用于对抗COVID-19。我们希望能找到更多的药物， SARS-CoV-2.

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.