Integrative transcriptomics analysis of lung epithelial cells and identification of repurposable drug candidates for COVID-19

Abstract

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.

Identification of candidate repurposable drugs to combat COVID-19 using a signature-based approach

“…S2 D). As expected, immune related pathways like interleukin signaling have also been reported by others following analysis of SARS-CoV-2 infection datasets 18 , 19 . Our workflow (modified) has also provided in silico confirmation of the anti-inflammatory and pro-immune effects of oxytocin 70 and the antidepressant fluoxetine 71 , which is also currently in trial for the treatment of COVID-19 (NCT04377308, and others).…”

“…Integrating the results of SARS-CoV-2 transcriptomic analyses generated in infected cell lines, human tissues and even organoids 16 with computational approaches has proven especially fruitful. Such studies identified FDA-approved antivirals 17 and a broad range of kinase inhibitors as potential candidate treatments for COVID-19 18 – 20 . Importantly, transcriptional analyses have provided additional support for the use of drugs like dexamethasone 17 and chlorpromazine 19 that are already undergoing clinical trial.…”

“…Importantly, transcriptional analyses have provided additional support for the use of drugs like dexamethasone 17 and chlorpromazine 19 that are already undergoing clinical trial. Analyzing the transcriptional changes induced by SARS-CoV-2 infection has also offered significant insight into the genes and biological pathways 17 , 18 , 21 – 23 that are altered in disease, implicating cellular inflammatory responses, particularly interferon pathways, in COVID-19 19 , 24 , 25 .…”

Diseasome and comorbidities complexities of SARS-CoV-2 infection with common malignant diseases

“…The chronic inflammation has been recognized as a causative factor for the progression of cancer [ 45 ]. Immune systems, cytokines overproduction and cytokine-mediated signaling provided key features in lung inflammation in response to COVID-19 infections [ 46 ], which are consistent with our findings. This study identified wnt signaling pathways, IL-17 signaling pathway, TNF signaling pathways as key signaling pathways associated with COVID-19 and cancers which is consistent with previous reports that identified these altered pathways in COVID-19 [ 46 ].…”

“…Immune systems, cytokines overproduction and cytokine-mediated signaling provided key features in lung inflammation in response to COVID-19 infections [ 46 ], which are consistent with our findings. This study identified wnt signaling pathways, IL-17 signaling pathway, TNF signaling pathways as key signaling pathways associated with COVID-19 and cancers which is consistent with previous reports that identified these altered pathways in COVID-19 [ 46 ]. Specifically, the “cytokine storm” seen in COVID-19 patients is the result of severe immune response by the host that deteriorate the conditions of the patients [ 46 ].…”