Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent of coronavirus disease-2019 (COVID-19), is a novel Betacoronavirus that was first reported in Wuhan, China in December of 2019. The virus has since caused a worldwide pandemic that highlights the need to quickly identify potential prophylactic or therapeutic treatments that can reduce the signs, symptoms, and/or spread of disease when dealing with a novel infectious agent. To combat this problem, Researchers from Brigham Young University constructed a computational pipeline that uniquely combines existing tools to predict drugs and biologics that could be repurposed to combat an emerging pathogen.
This workflow analyzes RNA-sequencing data to determine differentially expressed genes, enriched Gene Ontology (GO) terms, and dysregulated pathways in infected cells, which can then be used to identify US Food and Drug Administration (FDA)-approved drugs that target human proteins within these pathways. The researchers used this pipeline to perform a meta-analysis of RNA-seq data from cells infected with three Betacoronavirus species including severe acute respiratory syndrome coronavirus (SARS-CoV; SARS), Middle East respiratory syndrome coronavirus (MERS-CoV; MERS), and SARS-CoV-2, as well as respiratory syncytial virus and influenza A virus to identify therapeutics that could be used to treat COVID-19.
Infection with SARS-CoV-2 shows differential gene expression in Interleukin-6 signaling
This signaling pathway is a component of the larger Cytokine Signaling in Immune System pathway in Reactome. Each node represents a protein in the network, while each edge represents a characterized interaction between the proteins. Higher log2 fold-change values (up-regulation) are represented by increasing saturation of red, while more negative log2-fold-change values (down-regulation) are colored with increased saturation of blue. White nodes indicate no measured log2-fold change.
This analysis identified twelve existing drugs, most of which already have FDA-approval, that are predicted to counter the effects of SARS-CoV-2 infection. These results were cross-referenced with interventional clinical trials and other studies in the literature to identify drugs on the list that had previously been identified or used as treatments for COIVD-19 including canakinumab, anakinra, tocilizumab, sarilumab, and baricitinib.
While the results reported here are specific to Betacoronaviruses, such as SARS-CoV-2, our bioinformatics pipeline can be used to quickly identify candidate therapeutics for future emerging infectious diseases.
Availability – Code for this workflow can be found on GitHub: https://github.com/bpickett/Pathway2Targets.