{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:36:15Z","timestamp":1772156175966,"version":"3.50.1"},"reference-count":19,"publisher":"Microbiology Society","issue":"7","license":[{"start":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T00:00:00Z","timestamp":1689033600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"crossref","award":["282378"],"award-info":[{"award-number":["282378"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,11]]},"abstract":"<jats:p>\n                    The 2',5'- oligoadenylate synthetase (OAS) \u2013 ribonuclease L (RNAseL) - phosphodiesterase 12 (PDE12) pathway is an essential interferon-induced effector mechanism against RNA virus infection. Inhibition of PDE12 leads to selective amplification of RNAseL activity in infected cells. We aimed to investigate PDE12 as a potential pan-RNA virus antiviral drug target and develop PDE12 inhibitors that elicit antiviral activity against a range of viruses. A library of 18\u200a000 small molecules was screened for PDE12 inhibitor activity using a fluorescent probe specific for PDE12. The lead compounds (CO-17 or CO-63) were tested in cell-based antiviral assays using encephalomyocarditis virus (EMCV), hepatitis C virus (HCV), dengue virus (DENV), West Nile virus (WNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Cross reactivity of PDE12 inhibitors with other PDEs and\n                    <jats:italic>in vivo<\/jats:italic>\n                    toxicity were measured. In EMCV assays, CO-17 potentiated the effect of IFN\u03b1 by 3 log\n                    <jats:sub>10<\/jats:sub>\n                    . The compounds were selective for PDE12 when tested against a panel of other PDEs and non-toxic at up to 42\u2009mg\u202fkg\n                    <jats:sup>\u22121<\/jats:sup>\n                    in rats\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Thus, we have identified PDE12 inhibitors (CO-17 and CO-63), and established the principle that inhibitors of PDE12 have antiviral properties. Early studies suggest these PDE12 inhibitors are well tolerated at the therapeutic range, and reduce viral load in studies of DENV, HCV, WNV and SARS-CoV-2 in human cells and WNV in a mouse model.\n                  <\/jats:p>","DOI":"10.1099\/jgv.0.001865","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T12:17:20Z","timestamp":1689077840000},"source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of phosphodiesterase 12 results in antiviral activity against several RNA viruses including SARS-CoV-2"],"prefix":"10.1099","volume":"104","author":[{"given":"Mark","family":"Thursz","sequence":"first","affiliation":[{"name":"Department of Metabolism, Digestion and Reproduction, Imperial College, London W2 1NY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fouzia","family":"Sadiq","sequence":"additional","affiliation":[{"name":"Present address: Directorate of Research, Shifa Tameer-e-Millat University, Islamabad, Pakistan"},{"name":"Department of Metabolism, Digestion and Reproduction, Imperial College, London W2 1NY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia A.","family":"Tree","sequence":"additional","affiliation":[{"name":"UK Health Security Agency, Porton Down, Salisbury, SP4 0JG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5195-7863","authenticated-orcid":false,"given":"Peter","family":"Karayiannis","sequence":"additional","affiliation":[{"name":"University of Nicosia Medical School, Nicosia, Cyprus"},{"name":"RioTech Pharmaceuticals, 49 Arrivato Plaza, St Helens, WA10 1GH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David W. C.","family":"Beasley","sequence":"additional","affiliation":[{"name":"Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555-1019, USA"},{"name":"Centre for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-1019, USA"},{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555-1019, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanwissa","family":"Dejnirattisai","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, Old Road Campus, Oxford OX3 7BN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juthathip","family":"Mongkolsapaya","sequence":"additional","affiliation":[{"name":"Nuffield Department of Medicine, Old Road Campus, Oxford OX3 7BN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gavin","family":"Screaton","sequence":"additional","affiliation":[{"name":"Medical Science Division, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Wand","sequence":"additional","affiliation":[{"name":"UK Health Security Agency, Porton Down, Salisbury, SP4 0JG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Elmore","sequence":"additional","affiliation":[{"name":"UK Health Security Agency, Porton Down, Salisbury, SP4 0JG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miles W.","family":"Carroll","sequence":"additional","affiliation":[{"name":"UK Health Security Agency, Porton Down, Salisbury, SP4 0JG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8711-4838","authenticated-orcid":false,"given":"Ian","family":"Matthews","sequence":"additional","affiliation":[{"name":"RioTech Pharmaceuticals, 49 Arrivato Plaza, St Helens, WA10 1GH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Metabolism, Digestion and Reproduction, Imperial College, London W2 1NY, UK"},{"name":"RioTech Pharmaceuticals, 49 Arrivato Plaza, St Helens, WA10 1GH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"345","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2314"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400089200"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gene.6363984"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03065-y"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(10)60769-6"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2018.06.005"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-3670-0_3"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-021-00536-y"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.20798"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1038\/srep24530"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00316-07"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.653113"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.22.13308"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1282"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01312-14"},{"key":"R16","article-title":"Pde12 Mouse Gene Details","year":"2023"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1002\/prot.24794"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010930"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2022643118"}],"container-title":["Journal of General Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jgv\/10.1099\/jgv.0.001865?crawler=true&mimetype=application\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T03:22:26Z","timestamp":1689909746000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jgv\/10.1099\/jgv.0.001865"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,11]]},"references-count":19,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2023,7,11]]}},"URL":"https:\/\/doi.org\/10.1099\/jgv.0.001865","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.09.23.509178","asserted-by":"object"}]},"ISSN":["0022-1317","1465-2099"],"issn-type":[{"value":"0022-1317","type":"print"},{"value":"1465-2099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,11]]}}}