Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19

Henry C. Cousins, Adrienne Sarah Kline, Chengkun Wang, Yuanhao Qu, James Zengel, Jan Carette, Mengdi Wang, Russ B. Altman, Yuan Luo, Le Cong

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number100503
JournalCell Reports Methods
Volume3
Issue number7
DOIs
StatePublished - Jul 24 2023
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Biochemistry
  • Radiology Nuclear Medicine and imaging
  • Biotechnology
  • Computer Science Applications

Keywords

  • CP: Microbiology
  • CP: Systems biology

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