Integrative transcriptomics analysis of lung epithelial cells and identification of repurposable drug candidates for COVID-19.
Antiviral Agents
/ therapeutic use
COVID-19
Cells, Cultured
Computational Biology
Computer Simulation
Coronavirus Infections
/ drug therapy
Drug Repositioning
Epithelial Cells
/ drug effects
Gene Expression Regulation
/ genetics
Humans
Lung
/ cytology
Pandemics
Pneumonia, Viral
/ drug therapy
Signal Transduction
/ drug effects
Transcription Factors
/ genetics
Transcriptome
COVID-19
Drug repositioning,
SARS-CoV-2,transcriptomics
Journal
European journal of pharmacology
ISSN: 1879-0712
Titre abrégé: Eur J Pharmacol
Pays: Netherlands
ID NLM: 1254354
Informations de publication
Date de publication:
15 Nov 2020
15 Nov 2020
Historique:
received:
17
05
2020
revised:
09
09
2020
accepted:
21
09
2020
pubmed:
25
9
2020
medline:
6
11
2020
entrez:
24
9
2020
Statut:
ppublish
Résumé
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease, more commonly COVID-19 has emerged as a world health pandemic. There are couples of treatment methods for COVID-19, however, well-established drugs and vaccines are urgently needed to treat the COVID-19. The new drug discovery is a tremendous challenge; repurposing of existing drugs could shorten the time and expense compared with de novo drug development. In this study, we aimed to decode molecular signatures and pathways of the host cells in response to SARS-CoV-2 and the rapid identification of repurposable drugs using bioinformatics and network biology strategies. We have analyzed available transcriptomic RNA-seq COVID-19 data to identify differentially expressed genes (DEGs). We detected 177 DEGs specific for COVID-19 where 122 were upregulated and 55 were downregulated compared to control (FDR<0.05 and logFC ≥ 1). The DEGs were significantly involved in the immune and inflammatory response. The pathway analysis revealed the DEGs were found in influenza A, measles, cytokine signaling in the immune system, interleukin-4, interleukin -13, interleukin -17 signaling, and TNF signaling pathways. Protein-protein interaction analysis showed 10 hub genes (BIRC3, ICAM1, IRAK2, MAP3K8, S100A8, SOCS3, STAT5A, TNF, TNFAIP3, TNIP1). The regulatory network analysis showed significant transcription factors (TFs) that target DEGs, namely FOXC1, GATA2, YY1, FOXL1, NFKB1. Finally, drug repositioning analysis was performed with these 10 hub genes and showed that in silico validated three drugs with molecular docking. The transcriptomics signatures, molecular pathways, and regulatory biomolecules shed light on candidate biomarkers and drug targets which have potential roles to manage COVID-19. ICAM1 and TNFAIP3 were the key hubs that have demonstrated good binding affinities with repurposed drug candidates. Dabrafenib, radicicol, and AT-7519 were the top-scored repurposed drugs that showed efficient docking results when they tested with hub genes. The identified drugs should be further evaluated in molecular level wet-lab experiments in prior to clinical studies in the treatment of COVID-19.
Identifiants
pubmed: 32971089
pii: S0014-2999(20)30686-5
doi: 10.1016/j.ejphar.2020.173594
pmc: PMC7505772
pii:
doi:
Substances chimiques
Antiviral Agents
0
Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
173594Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
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