Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19.
Journal
Cell reports methods
ISSN: 2667-2375
Titre abrégé: Cell Rep Methods
Pays: United States
ID NLM: 9918227360606676
Informations de publication
Date de publication:
24 07 2023
24 07 2023
Historique:
received:
04
11
2022
revised:
01
04
2023
accepted:
23
05
2023
medline:
3
8
2023
pubmed:
2
8
2023
entrez:
2
8
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37529368
doi: 10.1016/j.crmeth.2023.100503
pii: S2667-2375(23)00132-7
pmc: PMC10243122
doi:
Substances chimiques
Spironolactone
27O7W4T232
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100503Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM141627
Pays : United States
Organisme : NHGRI NIH HHS
ID : R35 HG011316
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM145402
Pays : United States
Organisme : NLM NIH HHS
ID : R01 LM013337
Pays : United States
Informations de copyright
© 2023 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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