{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T22:40:38Z","timestamp":1778020838135,"version":"3.51.4"},"reference-count":31,"publisher":"Microbiology Society","issue":"12","license":[{"start":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T00:00:00Z","timestamp":1766102400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Council","award":["MR\/V036904\/1"],"award-info":[{"award-number":["MR\/V036904\/1"]}]},{"name":"COVID-19 Genomics UK Consortium"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,19]]},"abstract":"<jats:p>\n                    Coronaviruses such as SARS-CoV-2 possess the largest positive-sense RNA virus genomes (30\u2009kb). This poses a fidelity problem as the inherent lack of proof-reading capacity of the viral RNA-dependent RNA polymerase results in a high level of mutation. To overcome this issue, coronaviruses encode a 3\u2032\u22125\u2032 exoribonuclease (ExoN) proof-reading activity, which is a property of a complex of two non-structural proteins nsp14 and nsp10. Inactivating ExoN mutants in SARS-CoV-2 are lethal, indicating the importance of this enzymatic activity for virus replication and raising the possibility that small-molecule inhibitors of ExoN activity could be potential antiviral agents. To evaluate this, we used structure-based drug design approaches to identify potential ExoN inhibitors and tested these for activity against infectious SARS-CoV-2. Two compounds had low micromolar EC\n                    <jats:sub>50<\/jats:sub>\n                    activity and synergized with mutagenic nucleoside analogues. Next-generation sequencing analysis revealed an increased rate of mutation in the presence of these compounds, which is consistent with their mode of action being inhibition of ExoN enzymatic activity.\n                  <\/jats:p>","DOI":"10.1099\/jgv.0.002190","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T17:16:54Z","timestamp":1766164614000},"source":"Crossref","is-referenced-by-count":1,"title":["Identification and characterization of candidate inhibitors of the SARS-CoV-2 nsp14 3\u2032-5\u2032 exoribonuclease"],"prefix":"10.1099","volume":"106","author":[{"given":"Victoria","family":"Easton","sequence":"first","affiliation":[{"name":"School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin J.","family":"McPhillie","sequence":"additional","affiliation":[{"name":"School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor Andrade","family":"Santos","sequence":"additional","affiliation":[{"name":"Present address: The Pirbright Institute, Ash Road, Pirbright, Surrey, GU24 0NF, UK"},{"name":"School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippa","family":"Hall","sequence":"additional","affiliation":[{"name":"School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. Patrick","family":"McClure","sequence":"additional","affiliation":[{"name":"Wolfson Centre for Global Virus Research, University of Nottingham, Nottingham, NG7 2UH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart","family":"Astbury","sequence":"additional","affiliation":[{"name":"National Institute for Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, NG7 2UH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuelle","family":"Paci","sequence":"additional","affiliation":[{"name":"Present address: Department of Physics and Astronomy, University of Bologna, Viale Berti-Pichat 6\/2, 40125 Bologna BO, Italy"},{"name":"School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"St John","sequence":"additional","affiliation":[{"name":"Present address: Apoha, Nw Works Units 8 & 9, 135 Salusbury Rd, London NW6 6RJ, UK"},{"name":"School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin W.G.","family":"Fishwick","sequence":"additional","affiliation":[{"name":"School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9821-1003","authenticated-orcid":false,"given":"Mark","family":"Harris","sequence":"additional","affiliation":[{"name":"School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"345","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.001843"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.4161\/rna.8.2.15013"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1201130109"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.27009"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01246-20"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000896"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01296-07"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202300696"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2117-z"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012465330-6\/50003-8"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1101\/2024.06.26.24308604"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1021\/acsbiomedchemau.2c00046"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty191"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-018-1618-7"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1993.1626"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab320"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.3c01531"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003565"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.3390\/v14081790"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27092918"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001091"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100867"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiab483"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20210198"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1303"},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.647693"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.3390\/v15071539"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00900-1"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03101-9"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.106210"},{"key":"R31","doi-asserted-by":"publisher","DOI":"10.3390\/v14071413"}],"container-title":["Journal of General Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jgv\/10.1099\/jgv.0.002190?crawler=true&mimetype=application\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T17:16:55Z","timestamp":1766164615000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jgv\/10.1099\/jgv.0.002190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,19]]},"references-count":31,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12,19]]}},"URL":"https:\/\/doi.org\/10.1099\/jgv.0.002190","relation":{},"ISSN":["0022-1317","1465-2099"],"issn-type":[{"value":"0022-1317","type":"print"},{"value":"1465-2099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,19]]}}}