Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA.
Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Rep Methods. 2023 May 29;3(7):100503. doi: 10.1016/j.crmeth.2023.100503. eCollection 2023 Jul 24.
We demonstrate that integrative analysis of CRISPR screening datasets enables network-based prioritization of prescription drugs modulating viral entry in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by developing a network-based approach called Rapid proXimity Guidance for Repurposing Investigational Drugs (RxGRID). We use our results to guide a propensity-score-matched, retrospective cohort study of 64,349 COVID-19 patients, showing that a top candidate drug, spironolactone, is associated with improved clinical prognosis, measured by intensive care unit (ICU) admission and mechanical ventilation rates. Finally, we show that spironolactone exerts a dose-dependent inhibitory effect on viral entry in human lung epithelial cells. Our RxGRID method presents a computational framework, implemented as an open-source software package, enabling genomics researchers to identify drugs likely to modulate a molecular phenotype of interest based on high-throughput screening data. Our results, derived from this method and supported by experimental and clinical analysis, add additional supporting evidence for a potential protective role of the potassium-sparing diuretic spironolactone in severe COVID-19.
我们通过开发一种名为 RxGRID（Rapid proXimity Guidance for Repurposing Investigational Drugs）的基于网络的方法，证明了对 CRISPR 筛选数据集进行综合分析可以实现基于网络的对调节严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）病毒进入的处方药物的优先级排序。我们使用我们的结果来指导对 64349 名 COVID-19 患者的倾向评分匹配的回顾性队列研究，结果表明，一种顶级候选药物螺内酯与改善临床预后有关，表现在 ICU 入院和机械通气率方面。最后，我们表明螺内酯对人肺上皮细胞中的病毒进入具有剂量依赖性抑制作用。我们的 RxGRID 方法提供了一个计算框架，实现为开源软件包，使基因组学研究人员能够根据高通量筛选数据识别可能调节感兴趣的分子表型的药物。我们的结果源自该方法，并得到实验和临床分析的支持，为保钾利尿剂螺内酯在严重 COVID-19 中的潜在保护作用提供了额外的支持证据。
