{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T08:48:46Z","timestamp":1791622126274,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:00:00Z","timestamp":1791590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:00:00Z","timestamp":1791590400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFD2401101"],"award-info":[{"award-number":["2024YFD2401101"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010038","name":"Earmarked Fund for China Agriculture Research System","doi-asserted-by":"publisher","award":["CARS\u201045"],"award-info":[{"award-number":["CARS\u201045"]}],"id":[{"id":"10.13039\/501100010038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Fish Diseases"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Grass carp reovirus (GCRV) causes hemorrhagic disease in aquaculture, necessitating novel antivirals. Host\u2010targeted broad\u2010spectrum agents represent a promising approach. We evaluated Brequinar, a dihydroorotate dehydrogenase (DHODH) inhibitor in pyrimidine de novo synthesis, against GCRV in\u00a0vitro and in\u00a0vivo. In grass carp kidney (CIK) cells, Brequinar (0\u201350\u2009\u03bcM) showed no cytotoxicity, dose\u2010dependently alleviated cytopathic effect, reduced viral titers and suppressed VP5\/VP7 expression. Antiviral efficacy was observed under pre\u2010treatment, post\u2010treatment and 48\u2009h pre\u2010treatment regimens, with post\u2010infection administration showing stronger inhibition at moderate concentrations. In grass carp, Brequinar significantly reduced GCRV\u2010II\u2010induced mortality and tissue viral loads; post\u2010infection dosing conferred better survival. Pharmacokinetic analysis demonstrated markedly greater systemic and tissue exposure following intraperitoneal administration than oral gavage, with peak concentrations reaching 1493.09\u2009ng\/mL in blood and 931.13\u2009ng\/mL in liver after intraperitoneal injection, compared with only 114.8 and 105.6\u2009ng\/mL, respectively, following oral administration. Transcriptomics demonstrated broad downregulation of pyrimidine metabolism genes, validated by sorbitol dehydrogenase (SORD) suppression. In a 30\u2010day rare minnow model, Brequinar reduced viral loads after an initial rise, suggesting its potential application in reducing viral burden in virus\u2010infected broodstock. Collectively, Brequinar exerts anti\u2010GCRV activity by interfering with pyrimidine metabolism via DHODH inhibition and shows potential as a host\u2010targeted antiviral strategy, with possible application in reducing viral burden in high\u2010value broodstock in aquaculture.<\/jats:p>","DOI":"10.1111\/jfd.70300","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T08:03:15Z","timestamp":1791619395000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Brequinar Exerts Antiviral Effects Against Aquareovirus via Host Pyrimidine Metabolism Modulation"],"prefix":"10.1111","author":[{"given":"Linyi","family":"Liu","sequence":"first","affiliation":[{"name":"National Pathogen Collection Center for Aquatic Animals, College of Fisheries and Life Science Shanghai Ocean University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2213-3694","authenticated-orcid":false,"given":"Weijun","family":"Wu","sequence":"additional","affiliation":[{"name":"National Pathogen Collection Center for Aquatic Animals, College of Fisheries and Life Science Shanghai Ocean University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Han","sequence":"additional","affiliation":[{"name":"Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, College of Fisheries and Life Science Shanghai Ocean University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqun","family":"Lu","sequence":"additional","affiliation":[{"name":"National Pathogen Collection Center for Aquatic Animals, College of Fisheries and Life Science Shanghai Ocean University  Shanghai China"},{"name":"Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, College of Fisheries and Life Science Shanghai Ocean University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,10]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.06.075"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.000758"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.04745\u201022"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s42255-026-01454-7","article-title":"Ectopic Expression of Cytosolic DHODH Uncouples de Novo Pyrimidine Biosynthesis From Mitochondrial Electron Transport","volume":"8","author":"Curtabbi A.","year":"2026","journal-title":"Nature Metabolism"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2022.105403"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12250\u2010009\u20103028\u20101"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.054767\u20100"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.virusres.2022.198826","article-title":"Antiviral Activity of Brequinar Against African Swine Fever Virus Infection in Vitro","volume":"317","author":"Grigoryan R.","year":"2022","journal-title":"Virus Research"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2024.106008"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1101143108"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.04055\u201022"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01175\u201022"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009117"},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0969-2126(00)00077-0","article-title":"Structures of Human Dihydroorotate Dehydrogenase in Complex With Antiproliferative Agents","volume":"8","author":"Liu S.","year":"2000","journal-title":"Structure"},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1016\/0006-2952(92)90188-O","article-title":"The \u201cAnti\u2010Pyrimidine Effect\u201d of Hypoxia and Brequinar Sodium (NSC 368390) is of Consequence for Tumor Cell Growth","volume":"43","author":"L\u00f6ffler M.","year":"1992","journal-title":"Biochemical Pharmacology"},{"key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1023\/A:1006859115450","article-title":"Dihydroorotat\u2010Ubiquinone Oxidoreductase Links Mitochondria in the Biosynthesis of Pyrimidine Nucleotides","volume":"174","author":"L\u00f6ffler M.","year":"1997","journal-title":"Molecular and Cellular Biochemistry"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003678"},{"key":"e_1_2_11_19_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.antiviral.2025.106099","article-title":"DHODH Inhibitors: What Will It Take to Get Them Into the Clinic as Antivirals?","volume":"236","author":"Luganini A.","year":"2025","journal-title":"Antiviral Research"},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.antiviral.2018.08.012","article-title":"Inhibiting Pyrimidine Biosynthesis Impairs Ebola Virus Replication Through Depletion of Nucleoside Pools and Activation of Innate Immune Responses","volume":"158","author":"Luthra P.","year":"2018","journal-title":"Antiviral Research"},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10254-004-0025-5","article-title":"Recruitment of Hsp70 Chaperones: A Crucial Part of Viral Survival Strategies","volume":"153","author":"Mayer M.","year":"2005","journal-title":"Reviews of Physiology, Biochemistry and Pharmacology"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm301848w"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.11964\/jfc.20240114337"},{"key":"e_1_2_11_24_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.virusres.2018.01.005","article-title":"Targeting Heat Shock Protein 70 as an Antiviral Strategy Against Grass Carp Reovirus Infection","volume":"247","author":"Shan L.","year":"2018","journal-title":"Virus Research"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/v14102281"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.2174\/138955711797247707"},{"key":"e_1_2_11_27_1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.fsi.2019.12.047","article-title":"Grass Carp Reovirus Capsid Protein Interacts With Cellular Proteasome Subunit Beta\u2010Type 7: Evidence for the Involvement of Host Proteasome During Aquareovirus Infection","volume":"98","author":"Wang L.","year":"2020","journal-title":"Fish & Shellfish Immunology"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02333\u201012"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.684961"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01469\u201023"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238\u2010020\u201000768\u2010w"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11427\u2010015\u20104802\u2010y"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00494\u201024"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/v14050928"}],"container-title":["Journal of Fish Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jfd.70300","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jfd.70300","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jfd.70300","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T08:03:19Z","timestamp":1791619399000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jfd.70300"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,10]]},"references-count":33,"alternative-id":["10.1111\/jfd.70300"],"URL":"https:\/\/doi.org\/10.1111\/jfd.70300","archive":["Portico"],"relation":{},"ISSN":["0140-7775","1365-2761"],"issn-type":[{"value":"0140-7775","type":"print"},{"value":"1365-2761","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,10]]},"assertion":[{"value":"2026-09-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70300"}}