Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19.
Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19.
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DOI：
10.1016/j.crmeth.2023.100503
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发表时间：
2023-07-24
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我们通过开发一种称为重新利用研究药物的快速接近指导（RxGRID）的基于网络的方法，证明了对CRISPR筛选数据集的综合分析能够基于网络的处方药优先级调整严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的病毒进入。我们利用我们的结果指导了一项针对64,349名COVID-19患者的倾向评分匹配的回顾性队列研究，结果显示，首选候选药物螺内酯与临床预后改善有关，以重症监护病房（ICU）入院率和机械通气率来衡量。最后，我们表明螺内酯对病毒进入人肺上皮细胞有剂量依赖性的抑制作用。我们的RxGRID方法提供了一个计算框架，作为一个开源软件包实现，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。我们的结果来源于该方法，并得到实验和临床分析的支持，为保钾利尿剂螺内酯在重症COVID-19中的潜在保护作用提供了额外的支持证据。RxGRID发现螺内酯是SARS-CoV-2进入的潜在调节剂，在一项回顾性研究中，螺内酯与改善COVID-19结局相关。对现有COVID-19治疗具有耐药性和逃避先前疫苗接种的SARS-CoV-2变体的出现加强了对靶向宿主进入因子的药物的需求。尽管如此，目前仍缺乏系统、快速地确定病毒感染宿主靶向药物优先级的方法。高通量功能筛选为鉴定影响宿主细胞感染的基因提供了一种公正和广泛的方法。然而，从功能筛选数据推断药理学特征仍然具有挑战性。Cousins等人展示了一种基于功能基因组学筛选的候选药物优先排序的基于网络的方法。通过这种方法以及回顾性临床分析和体外病毒感染试验的随访，他们确定了保钾利尿剂螺内酯是SARS-CoV-2进入的潜在调节剂。
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. RxGRID is a method for network-based drug prioritization using CRISPR screening data RxGRID identifies spironolactone as a potential modulator of SARS-CoV-2 entry Spironolactone is associated with improved COVID-19 outcomes in a retrospective study The emergence of SARS-CoV-2 variants with resistance to existing COVID-19 treatments and evasion from prior vaccination reinforces the need for drugs targeting host entry factors. Nonetheless, there is a lack of methods that systematically and rapidly prioritize host-targeting drugs for viral infection. High-throughput functional screens provide an unbiased and broadly accessible means of identifying genes that influence the infection of host cells. However, it remains challenging to infer pharmacologic signatures from functional screening data. Cousins et al. demonstrate a network-based method for prioritizing drug candidates based on functional genomics screens. Using this approach and follow-up with both retrospective clinical analysis and in vitro viral infection assays, they identify the potassium-sparing diuretic spironolactone as a potential modulator of SARS-CoV-2 entry.
DOI：
10.3390/ph15020200
发表时间：
2022-02-05
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
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作者：
Kotfis K;Karolak I;Lechowicz K;Zegan-Barańska M;Pikulska A;Niedźwiedzka-Rystwej P;Kawa M;Sieńko J;Szylińska A;Wiśniewska M
通讯作者：
Wiśniewska M