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

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Precision Clinical Medicine 2021年第4期4卷 215-230页

作者： Zhihan Wang Kai Guo Pan Gao Qinqin Pu Changlong Li junguk hur Min Wu Department of Biomedical Sciences University of North Dakota School of Medicine and Health SciencesGrand ForksND 58202USA West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China Department of Neurology University of MichiganAnn ArborMI 48109USA Medical Research Institute Wuhan UniversityWuhan 430071China

Coronavirus disease 2019(COVID-19)has impacted almost every part of human lifeworldwide,posing amassive threat to human health.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 withmild 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).

关键词： COVID-19 drug repurposing SARS-CoV-2 influenza single-cell RNA sequencing adverse drug reaction Library of Integrated Network-Based Cellular Signatures sepsis post-transcription modifications

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