Discovering existing medicines that abrogate cellular responses to SARS CoV-2 infection

项目总结 我们的总体战略是筛选现有药物，看它们是否具有意想不到的能力来消除SARS的关键方面- 冠状病毒2型感染。该提案将利用我们作为Lincs财团的一部分创建的基础设施 使用基因表达谱来发现现有的药物，这些药物要么阻断了细胞机制，要么 病毒感染，或阻断细胞对导致疾病的感染的反应。虽然有很多生物学上的 学会做到这一点，这项提议的重点不是基础生物学，而是发现可以 在病人身上进行快速检测。出于这个原因，我们强调现有药物(那些FDA批准的， EMA批准的，或处于临床开发中)，因为它们可以推进到临床的速度 审判。我们建议的方法利用了我们共同基金支持的Lincs下开发的能力 转译中心。首先，我们创建了一个“随时可用”的生产级数据生成能力 现在，这一点可以在新冠肺炎上发挥作用。第二，我们已经组装了一个药物再利用文库 ~10,000种已获FDA批准或正在临床开发的药物。第三，通过我们Lincs的经验， 我们已经认识到，真正的力量来自于通过创造公众来释放世界科学界 其他人可以利用的资源。在这个项目中，我们将在肺上皮细胞和 单核细胞免疫细胞，使用基因表达谱作为读数。我们将使这种药物改变用途 LINCS数据集立即公开可用，因此研究社区中的任何人都可以使用 相关签名--包括那些尚未被发现的签名。通过以下途径确定的高优先级药物 对这些数据的分析将接受抗病毒和免疫功能的正交试验。一个重要的方面 这项提议的重点是创建一个新冠肺炎药物再利用门户，该门户将存放所有原始和 由该提案生成的处理数据，以及对生物学家友好的分析和可视化工具 将使整个新冠肺炎研究界能够确定临床前和最终的首要药物 作为抗新冠肺炎疗法的临床试验。

PROJECT SUMMARY Our overall strategy is to screen existing drugs for their unexpected ability to abrogate key aspects of SARS- CoV-2 infection. The proposal will leverage the infrastructure we have created as part of the LINCS Consortium to use gene expression profiling to discover existing drugs that either block the cellular mechanisms required for viral infection, or block the cellular response to infection that causes disease. While there is much biological learning to be done, the focus of this proposal is not basic biology, but rather on the discovery of drugs that could be rapidly tested in patients. For this reason, we emphasize existing drugs (those that are either FDA-approved, EMA-approved, or are in clinical development) because of the pace at which they can be advanced to clinical trials. Our proposed approach leverages capabilities developed under our Common Fund-supported LINCS Center for Transcriptomics. First, we have created a “shovel-ready” production-scale data generation capability that can now be brought to bear on COVID-19. Second, we have assembled a drug repurposing library with ~10,000 drugs that are either FDA-approved or are in clinical development. Third, through our LINCS experience, we have learned that real power comes from unleashing the world’s scientific community by creating public resources that can be utilized by others. In this project, we will screen ~10,000 drugs in lung epithelial cells and monocytic immune cells, using gene expression profiling as the readout. We will make this Drug Repurposing LINCS dataset immediately publicly available, so that anyone in the research community can query it with relevant signatures -- including those that have yet to be discovered. High priority drugs identified through analysis of these data will be subjected to orthogonal tests of antiviral and immune function. An important aspect of this proposal will be the creation of a COVID-19 Drug Repurposing Portal which will house all of the raw and processed data generated by this proposal, together with biologist-friendly analytical and visualization tools that will enable the entire COVID-19 research community to identify top priority drugs for pre-clinical and eventually clinical testing as anti-COVID-19 therapies.