TY - JOUR
T1 - Integrative analysis of functional genomic screening and clinical data identifies a protective role for spironolactone in severe COVID-19
AU - Cousins, Henry C.
AU - Kline, Adrienne Sarah
AU - Wang, Chengkun
AU - Qu, Yuanhao
AU - Zengel, James
AU - Carette, Jan
AU - Wang, Mengdi
AU - Altman, Russ B.
AU - Luo, Yuan
AU - Cong, Le
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/7/24
Y1 - 2023/7/24
N2 - 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.
AB - 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.
KW - CP: Microbiology
KW - CP: Systems biology
UR - http://www.scopus.com/inward/record.url?scp=85163354846&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85163354846&partnerID=8YFLogxK
U2 - 10.1016/j.crmeth.2023.100503
DO - 10.1016/j.crmeth.2023.100503
M3 - Article
C2 - 37529368
AN - SCOPUS:85163354846
SN - 2667-2375
VL - 3
JO - Cell Reports Methods
JF - Cell Reports Methods
IS - 7
M1 - 100503
ER -