{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:26:42Z","timestamp":1790270802293,"version":"4.1.0"},"reference-count":61,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T00:00:00Z","timestamp":1722556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["TR004529"],"award-info":[{"award-number":["TR004529"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Abraham and Linda Littenberg Foundation"},{"name":"DHR Endowment"},{"name":"UT Health San Antonio Dean\u2019s Fund"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The SARS-CoV-2 pandemic has caused unprecedented worldwide infections from persistent mutant variants with various degrees of infectivity and virulence. The elusiveness of a highly penetrant, worldwide vaccination strategy suggests that the complete eradication of SARS-CoV-2 is unlikely. Even with the advent of new antiviral agents, the disease burden worldwide continues to exceed current preventative and therapeutic strategies. Greater interest has been placed towards the development of affordable,broadly effective antiviral therapeutics. Here, we report that the small branched-chain fatty acid Valproic acid (VPA), approved for maintenance of seizure and bipolar disorder, has a novel anti- coronavirus activity that can be augmented with the addition of a long-chain, polyunsaturated omega-3 fatty acid, Docosahexaenoic acid (DHA). An EMR-based epidemiological study of patients tested for COVID-19 demonstrated a correlation exists between a reduced infection rate in patients treated withVPA of up to 25%, as well as a decreased risk of emergency room visits, hospitalization, ICU admission,and use of mechanical ventilation. <jats:italic>In vitro<\/jats:italic> studies have demonstrated that VPA modifies gene expression in MRC5 cells. Interestingly, VPA correlates with the inhibition of several SARS-CoV2 interacting genes and the greater inhibition of alpha-coronavirus HCoV-229E (a \u201ccommon cold\u201d virus) and SARS-CoV2. The VPA-DHA combination activates pre-existing intracellular antiviral mechanisms normally repressed by coronaviruses. Gene expression profiles demonstrate subtle differences in overall gene expression between VPA-treated and VPA-DHA-treated cells. HCoV-229E infection caused an intensely different response with a marked induction of multiple intracellular inflammatory genes. Changes in gene expression took at least 24 hours to manifest and most likely why prior drug screens failed to identify any antiviral VPA activity despite <jats:italic>in silico<\/jats:italic> predictions. This report demonstrates an interaction between HDAC inhibition and the potent activation of cellular antiviral responses. A foundation now exists for a low-cost, highly effective antiviral strategy when supplemented with DHA.<\/jats:p>","DOI":"10.1371\/journal.pone.0307154","type":"journal-article","created":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T17:26:15Z","timestamp":1722619575000},"page":"e0307154","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Valproic acid use is associated with diminished risk of contracting COVID-19, and diminished disease severity: Epidemiologic and in vitro analysis reveal mechanistic insights"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6893-1926","authenticated-orcid":true,"given":"Amanda","family":"Watson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankil","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doug","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitai","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1396-0153","authenticated-orcid":true,"given":"Geeta","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7724-7288","authenticated-orcid":true,"given":"Ediri","family":"Metitiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6731-646X","authenticated-orcid":true,"given":"Wasim H.","family":"Chowdhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Bacich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dube","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Hanley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Martinez-Sobrido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7592-1435","authenticated-orcid":true,"given":"Ronald","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,8,2]]},"reference":[{"key":"pone.0307154.ref001","first-page":"435","article-title":"Pharmacodynamic properties of N-dipropylacetic acid","volume":"18","author":"H Meunier","year":"1963","journal-title":"Therapie"},{"key":"pone.0307154.ref002","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1056\/NEJM198003203021204","article-title":"Drug therapy: Valproic acid","volume":"302","author":"J Koch-Weser","year":"1980","journal-title":"N Engl J Med"},{"issue":"Suppl 3","key":"pone.0307154.ref003","first-page":"11","article-title":"A medication algorithm for treatment of bipolar rapid cycling?","volume":"56","author":"JR Calabrese","year":"1995","journal-title":"J Clin Psychiatry"},{"key":"pone.0307154.ref004","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1177\/10600280221085991","article-title":"Valproate: Not All Boxed Warnings Are Created Equal","volume":"56","author":"C Wartman","year":"2022","journal-title":"Ann Pharmacother"},{"issue":"Suppl 1","key":"pone.0307154.ref005","first-page":"S91","article-title":"Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases","volume":"83","author":"M. G\u00f6ttlicher","year":"2004","journal-title":"Ann Hematol"},{"key":"pone.0307154.ref006","doi-asserted-by":"crossref","first-page":"7237","DOI":"10.1158\/0008-5472.CAN-05-0487","article-title":"Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo","volume":"66","author":"Q Xia","year":"2006","journal-title":"Cancer Res"},{"key":"pone.0307154.ref007","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1002\/pros.20587","article-title":"Multiple Molecular pathways explain the anti-proliferative effect of valproic acid on prostate cancer cells in vitro and in vivo","volume":"67","author":"S Shabbeer","year":"2007","journal-title":"Prostate"},{"key":"pone.0307154.ref008","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1111\/jcpt.12726","article-title":"Repurposing medications for use in treating HIV infection: A focus on valproic acid as a latency-reversing agent","volume":"43","author":"B Crosby","year":"2018","journal-title":"J Clin Pharm Ther"},{"key":"pone.0307154.ref009","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1128\/JVI.01717-10","article-title":"Inhibition of enveloped virus infection of cultured cells by valproic acid","volume":"85","author":"A V\u00e1zquez-Calvo","year":"2011","journal-title":"J Virol"},{"key":"pone.0307154.ref010","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":"583","author":"DE Gordon","year":"2020","journal-title":"Nature"},{"key":"pone.0307154.ref011","doi-asserted-by":"crossref","first-page":"23179","DOI":"10.1038\/s41598-021-02353-5","article-title":"Drug repurposing for COVID-19 using graph neural network and harmonizing multiple evidence","volume":"11","author":"K Hsieh","year":"2021","journal-title":"Sci Rep"},{"key":"pone.0307154.ref012","article-title":"Massive-scale biological activity-based modeling identifies novel antiviral leads against SARS-CoV-2","author":"R Huang","year":"2020","journal-title":"bioRxiv"},{"key":"pone.0307154.ref013","doi-asserted-by":"crossref","first-page":"e00819","DOI":"10.1128\/AAC.00819-20","article-title":"Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs","volume":"64","author":"S Jeon","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0307154.ref014","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/978-1-0716-1307-8_22","article-title":"iDEP Web Application for RNA-Seq Data Analysis","volume":"2284","author":"X. 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Acid in Prevention and Treatment of COVID-19"},{"key":"pone.0307154.ref054","article-title":"Valproic acid could help in the fight against COVID-19: A case\u2013control study","author":"O Moreno-P\u00e9rez","year":"2022","journal-title":"Neurologia"},{"key":"pone.0307154.ref055","doi-asserted-by":"crossref","first-page":"e0262777","DOI":"10.1371\/journal.pone.0262777","article-title":"Exposure to valproic acid is associated with less pulmonary infiltrates and improvements in diverse clinical outcomes and laboratory parameters in patients hospitalized with COVID-19","volume":"17","author":"J Collazos","year":"2022","journal-title":"PLoS One"},{"key":"pone.0307154.ref056","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1136\/bmjnph-2021-000250","article-title":"Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app","volume":"4","author":"P Louca","year":"2021","journal-title":"BMJ Nutr Prev 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Dietary Supplements and Nutraceuticals Under Investigation for COVID-19 Prevention and Treatment. 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