{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T16:08:46Z","timestamp":1777392526273,"version":"3.51.4"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,12,10]],"date-time":"2020-12-10T00:00:00Z","timestamp":1607558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2017YFC0908500"],"award-info":[{"award-number":["2017YFC0908500"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2016YFC1303205"],"award-info":[{"award-number":["2016YFC1303205"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970638"],"award-info":[{"award-number":["31970638"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["61572361"],"award-info":[{"award-number":["61572361"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Natural Science Foundation Program","award":["17ZR1449400"],"award-info":[{"award-number":["17ZR1449400"]}]},{"name":"Shanghai Artificial Intelligence Technology Standard Project","award":["19DZ2200900"],"award-info":[{"award-number":["19DZ2200900"]}]},{"name":"Shanghai Zhangjiang National Innovtaion Demonstration Zone","award":["ZJ2018-ZD-004"],"award-info":[{"award-number":["ZJ2018-ZD-004"]}]},{"name":"Institutions of Higher Learning in Shanghai"},{"name":"Zhejiang University and Fundamental Research Funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Emerging viral infections seriously threaten human health globally. Several challenges exist in identifying effective compounds against viral infections: (1) at the initial stage of a new virus outbreak, little information, except for its genome information, may be available; (2) although the identified compounds may be effective, they may be toxic in vivo and (3) cytokine release syndrome (CRS) triggered by viral infections is the primary cause of mortality. Currently, an integrative tool that takes all those aspects into consideration for identifying effective compounds to prevent viral infections is absent. In this study, we developed iDMer, as an integrative and mechanism-driven response system for addressing these challenges during the sudden virus outbreaks. iDMer comprises three mechanism-driven compound identification modules, that is, a virus-host interaction-oriented module, an autophagy-oriented module and a CRS-oriented module. As a one-stop integrative platform, iDMer incorporates compound toxicity evaluation and compound combination identification for virus treatment with clear mechanisms. iDMer was successfully tested on five viruses, including the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results indicated that, for all five tested viruses, compounds that were reported in the literature or experimentally validated for virus treatment were enriched at the top, demonstrating the generalized effectiveness of iDMer. Finally, we demonstrated that combinations of the individual modules successfully identified combinations of compounds effective for virus intervention with clear mechanisms.<\/jats:p>","DOI":"10.1093\/bib\/bbaa341","type":"journal-article","created":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T12:09:43Z","timestamp":1603886983000},"page":"976-987","source":"Crossref","is-referenced-by-count":16,"title":["iDMer: an integrative and mechanism-driven response system for identifying compound interventions for sudden virus outbreak"],"prefix":"10.1093","volume":"22","author":[{"given":"Zhiting","family":"Wei","sequence":"first","affiliation":[{"name":"School of Life Sciences and Technology, Tongji University, China"}]},{"given":"Yuli","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Technology, Tongji University, China"}]},{"given":"Fangliangzi","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Technology, Tongji University, China"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China"}]},{"given":"Yukang","family":"Gong","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Technology, Tongji University, China"}]},{"given":"Chenyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Life Sciences and Technology, Tongji University, China"}]},{"given":"Bin","family":"Ju","sequence":"additional","affiliation":[{"name":"Zhejiang Shuren University Shulan International Medical College"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China"}]},{"given":"Zhongmin","family":"Liu","sequence":"additional","affiliation":[{"name":"Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[{"name":"Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China"}]}],"member":"286","published-online":{"date-parts":[[2020,12,10]]},"reference":[{"key":"2021032314290275900_ref1","first-page":"174","article-title":"SARS-CoV-2, SARS-CoV, and MERS-COV: a comparative overview","volume":"28","author":"Rabaan","year":"2020","journal-title":"Infez Med"},{"key":"2021032314290275900_ref2","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nrd.2015.37","article-title":"Coronaviruses\u2014drug discovery and therapeutic options","volume":"15","author":"Zumla","year":"2016","journal-title":"Nat Rev Drug Discov"},{"key":"2021032314290275900_ref3","article-title":"Analysis of SARS-CoV-2-controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics","author":"Gassen","year":"2020","journal-title":"bioRxiv"},{"key":"2021032314290275900_ref4","doi-asserted-by":"crossref","first-page":"5770","DOI":"10.1038\/s41467-019-13659-4","article-title":"SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection","volume":"10","author":"Gassen","year":"2019","journal-title":"Nat Commun"},{"key":"2021032314290275900_ref5","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S0140-6736(20)30628-0","article-title":"COVID-19: consider cytokine storm syndromes and immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"Lancet"},{"key":"2021032314290275900_ref6","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41577-020-0308-3","article-title":"COVID-19: immunopathology and its implications for therapy","volume":"20","author":"Cao","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"2021032314290275900_ref7","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","article-title":"A next generation connectivity map: L1000 platform and the first 1,000,000 profiles","volume":"171","author":"Subramanian","year":"2017","journal-title":"Cell"},{"key":"2021032314290275900_ref8","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1126\/science.1132939","article-title":"The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease","volume":"313","author":"Molecules","year":"2006","journal-title":"Science"},{"key":"2021032314290275900_ref9","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2021032314290275900_ref10","article-title":"SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems","author":"Blanco-Melo","year":"2020","journal-title":"bioRxiv"},{"key":"2021032314290275900_ref11","doi-asserted-by":"crossref","first-page":"11.14.1","DOI":"10.1002\/0471250953.bi1114s51","article-title":"Mapping RNA-seq reads with STAR","volume":"51","author":"Dobin","year":"2015","journal-title":"Curr Protoc Bioinformatics"},{"key":"2021032314290275900_ref12","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"2021032314290275900_ref13","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"2021032314290275900_ref14","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"2021032314290275900_ref15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13073-014-0115-1","article-title":"Virus-host interactomics: new insights and opportunities for antiviral drug discovery","volume":"6","author":"Chassey","year":"2014","journal-title":"Genome Med"},{"key":"2021032314290275900_ref16","doi-asserted-by":"crossref","first-page":"D946","DOI":"10.1093\/nar\/gku1086","article-title":"EHFPI: a database and analysis resource of essential host factors for pathogenic infection","volume":"43","author":"Liu","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2021032314290275900_ref17","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3390\/v10100519","article-title":"Viruses.STRING: a virus-host protein-protein interaction database","volume":"10","author":"Cook","year":"2018","journal-title":"Viruses"},{"key":"2021032314290275900_ref18","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/s41586-020-2286-9","article-title":"A SARS-CoV-2 protein interaction map reveals targets for drug repurposing","volume":"538","author":"Gordon","year":"2020","journal-title":"Nature"},{"key":"2021032314290275900_ref19","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.csbj.2019.12.005","article-title":"Prediction of human-virus protein-protein interactions through a sequence embedding-based machine learning method","volume":"18","author":"Yang","year":"2020","journal-title":"Comput Struct Biotechnol J"},{"key":"2021032314290275900_ref20","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3390\/diseases4030026","article-title":"Human coronaviruses: a review of virus-host interactions","volume":"4","author":"Lim","year":"2016","journal-title":"Diseases"},{"key":"2021032314290275900_ref21","doi-asserted-by":"crossref","first-page":"D457","DOI":"10.1093\/nar\/gkv1070","article-title":"KEGG as a reference resource for gene and protein annotation","volume":"44","author":"Kanehisa","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2021032314290275900_ref22","doi-asserted-by":"crossref","first-page":"D691","DOI":"10.1093\/nar\/gkq1018","article-title":"Reactome: a database of reactions, pathways and biological processes","volume":"39","author":"Croft","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"2021032314290275900_ref23","first-page":"1","article-title":"Graph neural networks: a review of methods and applications","author":"Zhou","year":"2018"},{"key":"2021032314290275900_ref24","author":"Veli\u010dkovi\u0107"},{"key":"2021032314290275900_ref25","first-page":"249","article-title":"Understanding the difficulty of training deep feedforward neural networks","author":"Glorot","year":"2010","journal-title":"Proceedings of the thirteenth international conference on artificial intelligence and statistics"},{"key":"2021032314290275900_ref26","author":"Kingma"},{"key":"2021032314290275900_ref27","article-title":"Deep graph library: Towards efficient and scalable deep learning on graphs","author":"Wang"},{"key":"2021032314290275900_ref28","doi-asserted-by":"crossref","first-page":"D561","DOI":"10.1093\/nar\/gkq973","article-title":"The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored","volume":"39","author":"Szklarczyk","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"2021032314290275900_ref29","doi-asserted-by":"crossref","first-page":"W257","DOI":"10.1093\/nar\/gky318","article-title":"ProTox-II: a webserver for the prediction of toxicity of chemicals","volume":"46","author":"Banerjee","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2021032314290275900_ref30","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1128\/AAC.00976-10","article-title":"Combinatorial approaches to the prevention and treatment of HIV-1 infection","volume":"55","author":"Pirrone","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"key":"2021032314290275900_ref31","doi-asserted-by":"crossref","first-page":"E4304","DOI":"10.1073\/pnas.1803294115","article-title":"Deep learning improves prediction of drug\u2013drug and drug\u2013food interactions","volume":"115","author":"Ryu","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2021032314290275900_ref32","doi-asserted-by":"crossref","first-page":"104786","DOI":"10.1016\/j.antiviral.2020.104786","article-title":"Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro","volume":"178","author":"Choy","year":"2020","journal-title":"Antiviral Res"},{"key":"2021032314290275900_ref33","doi-asserted-by":"crossref","first-page":"6683","DOI":"10.1038\/srep06683","article-title":"Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib","volume":"4","author":"Pan","year":"2014","journal-title":"Sci Rep"},{"key":"2021032314290275900_ref34","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.antiviral.2018.04.016","article-title":"Novel activities of safe-in-human broad-spectrum antiviral agents","volume":"154","author":"Ianevski","year":"2018","journal-title":"Antiviral Res"},{"key":"2021032314290275900_ref35","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1021\/acsmedchemlett.7b00008","article-title":"Structure\u2013activity relationship study of QL47: a broad-spectrum antiviral agent","volume":"8","author":"Liang","year":"2017","journal-title":"ACS Med Chem Lett"},{"key":"2021032314290275900_ref36","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.csbj.2020.03.025","article-title":"Predicting commercially available antiviral drugs that may act on the novel coronavirus (SARS-CoV-2) through a drug-target interaction deep learning model","volume":"18","author":"Beck","year":"2020","journal-title":"Comput Struct Biotechnol J"},{"key":"2021032314290275900_ref37","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1110\/ps.083450408","article-title":"Characterization of ubiquitin and ubiquitin-like-protein isopeptidase activities","volume":"17","author":"Nicholson","year":"2008","journal-title":"Protein Sci"},{"key":"2021032314290275900_ref38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41421-020-0153-3","article-title":"Network-based drug repurposing for novel coronavirus 2019-nCoV\/SARS-CoV-2","volume":"6","author":"Zhou","year":"2020","journal-title":"Cell Discov"},{"key":"2021032314290275900_ref39","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.3390\/v4123440","article-title":"Involvement of autophagy in coronavirus replication","volume":"4","author":"Maier","year":"2012","journal-title":"Viruses"},{"key":"2021032314290275900_ref40","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41579-018-0003-6","article-title":"Autophagy during viral infection\u2014a double-edged sword","volume":"16","author":"Choi","year":"2018","journal-title":"Nat Rev Microbiol"},{"key":"2021032314290275900_ref41","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1126\/science.abb8925","article-title":"Cytokine release syndrome in severe COVID-19","volume":"368","author":"Moore","year":"2020","journal-title":"Science"},{"key":"2021032314290275900_ref42","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1634\/theoncologist.2018-0028","article-title":"FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome","volume":"23","author":"Le","year":"2018","journal-title":"Oncologist"},{"key":"2021032314290275900_ref43","doi-asserted-by":"crossref","first-page":"e208857","DOI":"10.1001\/jamanetworkopen.2020.8857","article-title":"Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial","volume":"3","author":"Borba","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2021032314290275900_ref44","doi-asserted-by":"crossref","first-page":"e00149","DOI":"10.1002\/prp2.149","article-title":"Analysis of drug combinations: current methodological landscape","volume":"3","author":"Foucquier","year":"2015","journal-title":"Pharmacol Res Perspect"},{"key":"2021032314290275900_ref45","article-title":"A transcriptional regulatory atlas of coronavirus infection of human cells","author":"Ochsner","year":"2020","journal-title":"bioRxiv"},{"key":"2021032314290275900_ref46","article-title":"Reversal of infected host gene expression identifies repurposed drug candidates for COVID-19","author":"Xing","year":"2020","journal-title":"bioRxiv"},{"key":"2021032314290275900_ref47","doi-asserted-by":"crossref","first-page":"16015","DOI":"10.1038\/npjsba.2016.15","article-title":"L1000CDS(2): LINCS L1000 characteristic direction signatures search engine","volume":"2","author":"Duan","year":"2016","journal-title":"NPJ Syst Biol Appl"},{"key":"2021032314290275900_ref48","doi-asserted-by":"crossref","first-page":"100037","DOI":"10.1016\/j.medidd.2020.100037","article-title":"Target virus or target ourselves for COVID-19 drugs discovery?\u2014lessons learned from anti-influenzas virus therapies","volume":"5","author":"Liao","year":"2020","journal-title":"Med Drug Discov"},{"key":"2021032314290275900_ref49","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/j.isci.2019.07.003","article-title":"The FDA-approved oral drug nitazoxanide amplifies host antiviral responses and inhibits Ebola virus","volume":"19","author":"Jasenosky","year":"2019","journal-title":"iScience"},{"key":"2021032314290275900_ref50","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1161\/ATVBAHA.119.313309","article-title":"Identification of emetine as a therapeutic agent for pulmonary arterial hypertension","volume":"39","author":"Hai","year":"2019","journal-title":"Arterioscler Thromb Vasc Biol"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/2\/976\/36655129\/bbaa341.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/bib\/article-pdf\/22\/2\/976\/36655129\/bbaa341.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T14:53:17Z","timestamp":1616511197000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/22\/2\/976\/6029312"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,10]]},"references-count":50,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,12,10]]},"published-print":{"date-parts":[[2021,3,22]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaa341","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,3]]},"published":{"date-parts":[[2020,12,10]]}}}