{"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":1772156175072,"version":"3.50.1"},"reference-count":38,"publisher":"Microbiology Society","issue":"7","license":[{"start":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T00:00:00Z","timestamp":1627603200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"crossref","award":["31003A_176170"],"award-info":[{"award-number":["31003A_176170"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"crossref","award":["31003A_182464"],"award-info":[{"award-number":["31003A_182464"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"crossref","award":["310030B_189363"],"award-info":[{"award-number":["310030B_189363"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,7,30]]},"abstract":"<jats:p>\n                    Rapid repurposing of existing drugs as new therapeutics for COVID-19 has been an important strategy in the management of disease severity during the ongoing SARS-CoV-2 pandemic. Here, we used high-throughput docking to screen 6000 compounds within the DrugBank library for their potential to bind and inhibit the SARS-CoV-2 3\u2009CL main protease, a chymotrypsin-like enzyme that is essential for viral replication. For 19 candidate hits, parallel\n                    <jats:italic>in vitro<\/jats:italic>\n                    fluorescence-based protease-inhibition assays and Vero-CCL81 cell-based SARS-CoV-2 replication-inhibition assays were performed. One hit, diclazuril (an investigational anti-protozoal compound), was validated as a SARS-CoV-2 3\u2009CL main protease inhibitor\n                    <jats:italic>in vitro<\/jats:italic>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    value of 29\u2009\u00b5M) and modestly inhibited SARS-CoV-2 replication in Vero-CCL81 cells. Another hit, lenvatinib (approved for use in humans as an anti-cancer treatment), could not be validated as a SARS-CoV-2 3\u2009CL main protease inhibitor\n                    <jats:italic>in vitro<\/jats:italic>\n                    , but serendipitously exhibited a striking functional synergy with the approved nucleoside analogue remdesivir to inhibit SARS-CoV-2 replication, albeit this was specific to Vero-CCL81 cells. Lenvatinib is a broadly-acting host receptor tyrosine kinase (RTK) inhibitor, but the synergistic effect with remdesivir was not observed with other approved RTK inhibitors (such as pazopanib or sunitinib), suggesting that the mechanism-of-action is independent of host RTKs. Furthermore, time-of-addition studies revealed that lenvatinib\/remdesivir synergy probably targets SARS-CoV-2 replication subsequent to host-cell entry. Our work shows that combining computational and cellular screening is a means to identify existing drugs with repurposing potential as antiviral compounds. Future studies could be aimed at understanding and optimizing the lenvatinib\/remdesivir synergistic mechanism as a therapeutic option.\n                  <\/jats:p>","DOI":"10.1099\/jgv.0.001625","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T12:16:16Z","timestamp":1627474576000},"source":"Crossref","is-referenced-by-count":4,"title":["Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir"],"prefix":"10.1099","volume":"102","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9876-3836","authenticated-orcid":false,"given":"Marie O.","family":"Pohl","sequence":"first","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8781-9099","authenticated-orcid":false,"given":"Idoia","family":"Busnadiego","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8534-2442","authenticated-orcid":false,"given":"Francesco","family":"Marrafino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Fisciano SA, 84084, Italy"},{"name":"Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Wiedmer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Hunziker","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3362-3832","authenticated-orcid":false,"given":"Sonja","family":"Fernbach","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6976-6360","authenticated-orcid":false,"given":"Irina","family":"Glas","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6485-3481","authenticated-orcid":false,"given":"Elena V.","family":"Moroz-Omori","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3891-9480","authenticated-orcid":false,"given":"Benjamin G.","family":"Hale","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2317-6792","authenticated-orcid":false,"given":"Amedeo","family":"Caflisch","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9491-2892","authenticated-orcid":false,"given":"Silke","family":"Stertz","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"345","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30120-1"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001017"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.2648"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30183-5"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2021.03.001"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2034577"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2035389"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32661-1"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2798-3"},{"key":"R10","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2023184","article-title":"repurposed antiviral drugs for covid-19 - interim WHO solidarity trial results","volume":"384","author":"Pan","year":"2021","journal-title":"N Engl J Med"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2007764"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2577-1"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe9403"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-00468-6"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1126\/science.1085658"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb3405"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18709-w"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.3851\/IMP2127"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2009.10.003"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1101\/2020.08.31.274639"},{"key":"R21","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00872-20","article-title":"Discovery of M protease inhibitors encoded by SARS-CoV-2","volume":"64","author":"Hung","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"R22","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-18233-x","article-title":"Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease","volume":"11","author":"Fu","year":"2020","journal-title":"Nat Commun"},{"key":"R23","article-title":"Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication","volume":"11","author":"Vuong","year":"2020","journal-title":"Nat Commun"},{"key":"R24","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: a major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001006"},{"key":"R26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107940"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S188316"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1177\/1073274818789361"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16954-7"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0134(20010201)42:2<256::aid-prot130>3.0.co;2-4"},{"key":"R31","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0134(19991001)37:1<88::AID-PROT9>3.0.CO;2-O"},{"key":"R32","doi-asserted-by":"publisher","DOI":"10.1021\/jp9714227"},{"key":"R33","doi-asserted-by":"publisher","DOI":"10.1021\/jp973084f"},{"key":"R34","doi-asserted-by":"publisher","DOI":"10.1021\/ja036959e"},{"key":"R35","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.21367"},{"key":"R36","article-title":"Hydrogen bonding penalty upon ligand binding","volume":"6","author":"Zhao","year":"2011","journal-title":"Plos One"},{"key":"R37","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.01928-20"},{"key":"R38","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1089"}],"container-title":["Journal of General Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jgv\/10.1099\/jgv.0.001625?crawler=true&mimetype=application\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T17:28:35Z","timestamp":1702574915000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jgv\/10.1099\/jgv.0.001625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,30]]},"references-count":38,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2021,7,30]]}},"URL":"https:\/\/doi.org\/10.1099\/jgv.0.001625","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.03.19.435806","asserted-by":"object"}]},"ISSN":["0022-1317","1465-2099"],"issn-type":[{"value":"0022-1317","type":"print"},{"value":"1465-2099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,30]]}}}