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Computational analysis to repurpose drugs for COVID-19 based on transcriptional response of host cells to SARS-CoV-2
Fuhai Li1,2, Andrew P Michelson3,4, Randi Foraker3
1Institute for Informatics (I2), Washington University in St. Louis School of Medicine, St. Louis, MO, USA. Fuhai.Li@wustl.edu.
Background:
The Coronavirus Disease 2019 (COVID-19) pandemic has infected over 10 million people globally with a relatively high mortality rate. There are many therapeutics undergoing clinical trials, but there is no effective vaccine or therapy for treatment thus far. After affected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), molecular signaling pathways of host cells play critical roles during the life cycle of SARS-CoV-2. Thus, it is significant to identify the involved molecular signaling pathways within the host cells. Drugs targeting these molecular signaling pathways could be potentially effective for COVID-19 treatment.
Methods:
In this study, we developed a novel integrative analysis approach to identify the related molecular signaling pathways within host cells, and repurposed drugs as potentially effective treatments for COVID-19, based on the transcriptional response of host cells.
Results:
We identified activated signaling pathways associated with the infection caused SARS-CoV-2 in human lung epithelial cells through integrative analysis. Then, the activated gene ontologies (GOs) and super GOs were identified. Signaling pathways and GOs such as MAPK, JNK, STAT, ERK, JAK-STAT, IRF7-NFkB signaling, and MYD88/CXCR6 immune signaling were particularly activated. Based on the identified signaling pathways and GOs, a set of potentially effective drugs were repurposed by integrating the drug-target and reverse gene expression data resources. In addition to many drugs being evaluated in clinical trials, the dexamethasone was top-ranked in the prediction, which was the first reported drug to be able to significantly reduce the death rate of COVID-19 patients receiving respiratory support.
Conclusions:
The integrative genomics data analysis and results can be helpful to understand the associated molecular signaling pathways within host cells, and facilitate the discovery of effective drugs for COVID-19 treatment.
Insights
This study identifies key molecular pathways activated by SARS-CoV-2 infection in lung cells. Repurposed drugs targeting these pathways, including dexamethasone, show potential for effective COVID-19 treatment.
Area of Science:
- Genomics
- Infectious Disease Research
- Drug Repurposing
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, has a high mortality rate with no definitive treatments.
- Host cell molecular signaling pathways are crucial for SARS-CoV-2 replication.
- Identifying these pathways is key to developing effective COVID-19 therapies.
Purpose of the Study:
- To identify molecular signaling pathways involved in SARS-CoV-2 infection within host cells.
- To repurpose existing drugs as potential treatments for COVID-19 based on host cell transcriptional responses.
Main Methods:
- Developed a novel integrative analysis approach.
- Analyzed transcriptional responses of human lung epithelial cells upon SARS-CoV-2 infection.
- Integrated drug-target and reverse gene expression data for drug repurposing.
Main Results:
- Identified activated signaling pathways including MAPK, JNK, STAT, ERK, JAK-STAT, and IRF7-NFkB immune signaling.
- Repurposed drugs based on identified pathways and gene ontologies.
- Dexamethasone was top-ranked, showing significant reduction in mortality for supported COVID-19 patients.
Conclusions:
- Integrative analysis aids understanding of host-pathogen molecular interactions.
- Facilitates the discovery of effective drugs for COVID-19 treatment.
- Highlights dexamethasone as a promising therapeutic option.
