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 language | English (US) |
|---|---|
| Article number | 100503 |
| Journal | Cell Reports Methods |
| Volume | 3 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 24 2023 |
Funding
This work was supported by the National Institutes of Health ( GM007365 and GM145402 to H.C.C., GM102365 to R.B.A., LM013337 to Y.L., GM141627 and HG011316 to L.C.), by the Donald and Delia Baxter Foundation (to L.C.), by the National Science Foundation ( 1953686 to M.W.), by the Knight-Hennessy Scholarships (to H.C.C.), and by a kind gift from the Weintz Family (to L.C.). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript. Figure 1 and the graphical abstract were created using BioRender. This work was supported by the National Institutes of Health (GM007365 and GM145402 to H.C.C. GM102365 to R.B.A. LM013337 to Y.L. GM141627 and HG011316 to L.C.), by the Donald and Delia Baxter Foundation (to L.C.), by the National Science Foundation (1953686 to M.W.), by the Knight-Hennessy Scholarships (to H.C.C.), and by a kind gift from the Weintz Family (to L.C.). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data or in writing the manuscript. Figure 1 and the graphical abstract were created using BioRender. Conceptualization, H.C.C. L.C. and R.B.A.; methodology, H.C.C. A.S.K. C.W. Y.Q. J.Z. J.C. and L.C.; software, H.C.C. and A.S.K.; formal analysis, H.C.C. A.S.K. and L.C.; investigation, H.C.C. A.S.K. C.W. Y.Q. and J.Z.; resources, R.B.A. Y.L. and L.C.; writing \u2013 original draft, H.C.C. A.S.K. R.B.A. and L.C.; writing \u2013 review & editing, H.C.C. A.S.K. and L.C.; supervision, J.C. M.W. R.B.A. Y.L. and L.C. The authors declare no competing interests. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a gender minority in their field of research.
Keywords
- CP: Microbiology
- CP: Systems biology
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Genetics
- Radiology Nuclear Medicine and imaging
- Computer Science Applications
