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

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The lack of time for new drug discovery and the urgent need for rapid disease control to reduce mortality have led to a search for quick and effective alternatives to novel therapeutics, for example drug repurposing. 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 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 patients with mild and severe COVID-19 (GEO: GSE145926, public data available and accessed on 22 April 2020). We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2 (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).", "claims": [{"id": "claim-method", "statement": "MAST, a generalized linear model framework treating the cellular detection rate as a covariate, was used to perform differential analysis.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34993416", "locator": "sections[5] \"Differential analysis for clusters among the three groups\" paragraph 2", "quote": "MAST, a generalized linear model framework treating the cellular detection rate as a covariate, was used to perform differential analysis."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The scRNA-seq and bulk-RNA-seq data are available from the NCBI Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/; accession ID: GSE145926) and the Chinese National Genomics Data Center (https://bigd.big.ac.cn/; accession ID: CRA002390), respectively. All the codes used in this study are available at https://github.com/guokai8/COVID19/.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34993416", "locator": "sections[25] \"Data availability\" paragraph 2", "quote": "The scRNA-seq and bulk-RNA-seq data are available from the NCBI Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/; accession ID: GSE145926) and the Chinese National Genomics Data Center (https://bigd.big.ac.cn/; accession ID: CRA002390), respectively. All the codes used in this study are available at https://github.com/guokai8/COVID19/."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The study identified 281 FDA-approved drugs with potential efficacy against SARS-CoV-2 infection, including 16 drugs undergoing clinical trials for COVID-19.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:34993416", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The study identified 281 FDA-approved drugs with potential efficacy against SARS-CoV-2 infection, including 16 drugs undergoing clinical trials for COVID-19.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:34993416"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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