{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T13:20:48Z","timestamp":1742390448854,"version":"3.37.3"},"update-to":[{"updated":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"DOI":"10.1371\/journal.pcbi.1011050","type":"new_version","source":"publisher","label":"New version"}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T00:00:00Z","timestamp":1683244800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006502","name":"Defense Sciences Office, DARPA","doi-asserted-by":"publisher","award":["HR0011-20-2-0040"],"id":[{"id":"10.13039\/100006502","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016528","name":"Hansj\u00f6rg Wyss Institute for Biologically Inspired Engineering, Harvard University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016528","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Christopher Hess Research Fund"},{"name":"University of California, San Francisco, Program for Breakthrough Biomedical Research grant"},{"name":"Medical Scientist Training Program","award":["T32GM007618"]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM138353"],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit. A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. Simvastatin was among the most highly predicted compounds (14\/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro<\/jats:italic> testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011050","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T17:39:44Z","timestamp":1683308384000},"page":"e1011050","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Target-agnostic drug prediction integrated with medical record analysis uncovers differential associations of statins with increased survival in COVID-19 patients"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8310-5358","authenticated-orcid":true,"given":"Megan M.","family":"Sperry","sequence":"first","affiliation":[]},{"given":"Tomiko 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FDA Approves First Treatment for COVID-19. In: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-treatment-covid-19. 22 Oct 2020.","DOI":"10.1002\/cpu.30542"},{"key":"pcbi.1011050.ref038","unstructured":"US Food & Drug Administration. FDA Takes Actions to Expand Use of Treatment for Outpatients with Mild-to-Moderate COVID-19. 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Tuning up transplantation Graft-versus-host disease: suppression by statins. 2008. http:\/\/www.nature.com\/naturemedicine","DOI":"10.1038\/nm1108-1155"},{"key":"pcbi.1011050.ref048","doi-asserted-by":"crossref","first-page":"636","DOI":"10.3390\/antiox9070636","article-title":"Genetic Polymorphisms Complicate COVID-19 Therapy: Pivotal Role of HO-1 in Cytokine Storm","volume":"9","author":"EW Fakhouri","year":"2020","journal-title":"Antioxidants"},{"key":"pcbi.1011050.ref049","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0024394","article-title":"Studies on the antibacterial effects of statins\u2014in vitro and in vivo","volume":"6","author":"P Bergman","year":"2011","journal-title":"PLoS One"},{"key":"pcbi.1011050.ref050","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1159\/000516862","article-title":"Statin Intake and All-Cause Mortality among Older Nursing Home Residents","volume":"68","author":"A de Spiegeleer","year":"2022","journal-title":"Gerontology"},{"volume-title":"UpToDate","year":"2021","author":"RS Rosenson","key":"pcbi.1011050.ref051"}],"updated-by":[{"updated":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"DOI":"10.1371\/journal.pcbi.1011050","type":"new_version","source":"publisher","label":"New version"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011050","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T17:47:02Z","timestamp":1684345622000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011050"}},"subtitle":[],"editor":[{"given":"Teresa M.","family":"Przytycka","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2023,5,5]]},"references-count":51,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011050","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.04.12.22273802","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"type":"electronic","value":"1553-7358"}],"subject":[],"published":{"date-parts":[[2023,5,5]]}}}