Repurposable drugs for SARS-CoV-2 and influenza sepsis with scRNA-seq data targeting post-transcription modifications

Abstract

Coronavirus disease 2019 (COVID-19) has been impacting almost every part of human life worldwide, posing a massive threat to human health. Due to the lack of time for new drug discovery and the urgent need for rapid disease control, drug repurposing presents a quick and effective alternative to finding therapeutics to reduce mortality. To identify potentially repurposable drugs, we employed a systematic approach to mine candidates from U.S. FDA-approved drugs and preclinical small-molecule compounds by integrating the gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from mild and severe COVID-19 patients (GEO: GSE145926, public data available and accessed on April 22, 2020). We identified 281 FDA-approved drugs that have the potential to be effective against SARS-CoV-2 infection, 16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19. We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a, two chemical inhibitors of glycosylation (a post-translational modification) on the replication of the single-stranded ribonucleic acid (ssRNA) virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators (IFNs and ISGs). In conclusion, we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach, which may have the potential for treating these viral infections and their complications (sepsis).

Delineating COVID-19 immunological features using single-cell RNA sequencing

“…Furthermore, there are many other studies using scRNA-seq from COVID-19 patients to conduct therapeutic drug development or validation. 81,83,84 Many studies explored the post-COVID-19 symptoms by cytokine storm on diverse organs by using scRNA-seq and other omics data. 2,85 Mutual corroboration of results in transcriptomics and other omics substantially improves the reliability of new findings, which has been more recognized in the current COVID-19 research.…”

Phase II, Double-Blinded, Randomized, Placebo-Controlled Clinical Trial Investigating the Efficacy of Mebendazole in the Management of Symptomatic COVID-19 Patients

“…Several antiviral agents capable of managing COVID-19 hospitalizations have been investigated, including remdesivir, ritonavir, interferon, corticosteroids, cytokine storm blockers, and monoclonal antibodies, with similar results in mild to moderate COVID-19 patients [ 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. Since no pharmacological agent has a well-established COVID-19 eradication effect that is effective, rapid, and inexpensive, it was crucial to evaluate a new potential anthelmintic agents with antiviral properties such as mebendazole in a prospective setting [ 48 , 49 , 50 , 51 ].…”

scRNA-Seq-based drug repurposing targeting idiopathic pulmonary fibrosis (IPF)

“…Matching results are then available for each cluster, and a final drug ranking can then be obtained, e.g. by giving higher priority to compounds detected in multiple clusters, which was implemented by Wang et al 23 , or by summarising to an overall score, as implemented in ASGARD (A Single-cell Guided pipeline to Aid Repurposing of Drugs) 24 .…”

“…The approach we revisit in this study towards this aim is signature matching to identify compounds inducing perturbation responses which match a defined disease signature. Previous studies applying signature matching to scRNA-Seq data follow the idea of reversing the diseased state to individual cell clusters instead of bulk expression, which mitigates compositional changes as covariate 23,24 . Matching results are then available for each cluster, and a final drug ranking can then be obtained, e.g.…”