{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:44:38Z","timestamp":1792046678939,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012571","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000}}],"reference-count":70,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004497","name":"Onderzoeksraad, KU Leuven","doi-asserted-by":"publisher","award":["C24E\/22\/035"],"award-info":[{"award-number":["C24E\/22\/035"]}],"id":[{"id":"10.13039\/501100004497","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020098","name":"Innovative Health Initiative","doi-asserted-by":"publisher","award":["101005077"],"award-info":[{"award-number":["101005077"]}],"id":[{"id":"10.13039\/100020098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008666","name":"Fundaci\u00f3 la Marat\u00f3 de TV3","doi-asserted-by":"publisher","award":["201832 and 202135"],"award-info":[{"award-number":["201832 and 202135"]}],"id":[{"id":"10.13039\/100008666","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FWO Research Foundation Flanders","award":["1S66321"],"award-info":[{"award-number":["1S66321"]}]},{"name":"FWO Research Foundation Flanders","award":["1S21225N"],"award-info":[{"award-number":["1S21225N"]}]},{"name":"FWO Research Foundation Flanders","award":["1162823N"],"award-info":[{"award-number":["1162823N"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>The approval of COVID-19 vaccines and antiviral drugs has been crucial to end the global health crisis caused by SARS-CoV-2. However, to prepare for future outbreaks from drug-resistant variants and novel zoonotic coronaviruses (CoVs), additional therapeutics with a distinct antiviral mechanism are needed. Here, we report a novel guanidine-substituted diphenylurea compound that suppresses CoV replication by interfering with the uridine-specific endoribonuclease (EndoU) activity of the viral non-structural protein-15 (nsp15). This compound, designated EPB-113, exhibits strong and selective cell culture activity against human coronavirus 229E (HCoV-229E) and also suppresses the replication of SARS-CoV-2. Viruses, selected under EPB-113 pressure, carried resistance sites at or near the catalytic His250 residue of the nsp15-EndoU domain. Although the best-known function of EndoU is to avoid induction of type I interferon (IFN-I) by lowering the levels of viral dsRNA, EPB-113 was found to mainly act via an IFN-independent mechanism, situated during viral RNA synthesis. Using a combination of biophysical and enzymatic assays with the recombinant nsp15 proteins from HCoV-229E and SARS-CoV-2, we discovered that EPB-113 enhances the EndoU cleavage activity of hexameric nsp15, while reducing its thermal stability. This mechanism explains why the virus escapes EPB-113 by acquiring catalytic site mutations which impair compound binding to nsp15 and abolish the EndoU activity. Since the EPB-113-resistant mutant viruses induce high levels of IFN-I and its effectors, they proved unable to replicate in human macrophages and were readily outcompeted by the wild-type virus upon co-infection of human fibroblast cells. Our findings suggest that antiviral targeting of nsp15 can be achieved with a molecule that induces a conformational change in this protein, resulting in higher EndoU activity and impairment of viral RNA synthesis. Based on the appealing mechanism and resistance profile of EPB-113, we conclude that nsp15 is a challenging but highly relevant drug target.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012571","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T13:38:36Z","timestamp":1739281116000},"page":"e1012571","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["A guanidine-based coronavirus replication inhibitor which targets the nsp15 endoribonuclease and selects for interferon-susceptible mutant viruses"],"prefix":"10.1371","volume":"21","author":[{"given":"Benjamin","family":"Van Loy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eug\u00e8nia","family":"Pujol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Kamata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao Yin","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolai","family":"Bakirtzoglou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ria","family":"Van Berwaer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Vandeput","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cato","family":"Mestdagh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leentje","family":"Persoons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent","family":"De Wijngaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quinten","family":"Goovaerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Noppen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten","family":"Jacquemyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kourosh","family":"Ahmadzadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eline","family":"Bernaerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Mart\u00edn-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Escriche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"Vanmechelen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Besir","family":"Krasniqi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhimanyu K.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Daelemans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piet","family":"Maes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Matthys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim","family":"Dehaen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jef","family":"Rozenski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalyan","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnout","family":"Voet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"V\u00e1zquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9742-9302","authenticated-orcid":true,"given":"Lieve","family":"Naesens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"Stevaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"ppat.1012571.ref001","unstructured":"World Health Organization. WHO COVID-19 dashboard. [cited 2025 Jan 08]. Available from: https:\/\/data.who.int\/dashboards\/covid19\/cases."},{"key":"ppat.1012571.ref002","unstructured":"Infectious Diseases Society of America. IDSA guidelines on the treatment and management of patients with COVID-19. [cited 2024 Aug 23]. Available from: https:\/\/www.idsociety.org\/COVID19guidelines#null."},{"issue":"3","key":"ppat.1012571.ref003","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","article-title":"Coronavirus biology and replication: implications for SARS-CoV-2","volume":"19","author":"P V\u2019Kovski","year":"2021","journal-title":"Nat Rev Microbiol"},{"key":"ppat.1012571.ref004","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1146\/annurev-biochem-052521-115653","article-title":"The life of SARS-CoV-2 inside cells: replication-transcription complex assembly and function","volume":"91","author":"Z Lou","year":"2022","journal-title":"Annu Rev Biochem"},{"issue":"6","key":"ppat.1012571.ref005","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/s41573-023-00672-y","article-title":"Therapeutic strategies for COVID-19: progress and lessons learned","volume":"22","author":"G Li","year":"2023","journal-title":"Nat Rev Drug Discov"},{"issue":"3","key":"ppat.1012571.ref006","first-page":"178","article-title":"Innate immune evasion strategies of SARS-CoV-2","volume":"21","author":"JM Minkoff","year":"2023","journal-title":"Nat Rev Microbiol"},{"issue":"34","key":"ppat.1012571.ref007","doi-asserted-by":"crossref","first-page":"12694","DOI":"10.1073\/pnas.0403127101","article-title":"Major genetic marker of nidoviruses encodes a replicative endoribonuclease","volume":"101","author":"KA Ivanov","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ppat.1012571.ref008","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.virol.2017.12.024","article-title":"An \u201cold\u201d protein with a new story: coronavirus endoribonuclease is important for evading host antiviral defenses","volume":"517","author":"X Deng","year":"2018","journal-title":"Virology"},{"issue":"12","key":"ppat.1012571.ref009","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1261\/rna.076604.120","article-title":"Physiologic RNA targets and refined sequence specificity of coronavirus EndoU","volume":"26","author":"R Ancar","year":"2020","journal-title":"RNA"},{"issue":"21","key":"ppat.1012571.ref010","doi-asserted-by":"crossref","first-page":"E4251","DOI":"10.1073\/pnas.1618310114","article-title":"Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages","volume":"114","author":"X Deng","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"ppat.1012571.ref011","doi-asserted-by":"crossref","first-page":"e1006195","DOI":"10.1371\/journal.ppat.1006195","article-title":"Early endonuclease-mediated evasion of RNA sensing ensures efficient coronavirus replication","volume":"13","author":"E Kindler","year":"2017","journal-title":"PLoS Pathog"},{"issue":"14","key":"ppat.1012571.ref012","doi-asserted-by":"crossref","first-page":"8094","DOI":"10.1073\/pnas.1921485117","article-title":"Coronavirus endoribonuclease targets viral polyuridine sequences to evade activating host sensors","volume":"117","author":"M Hackbart","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"issue":"7816","key":"ppat.1012571.ref013","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"},{"issue":"9","key":"ppat.1012571.ref014","doi-asserted-by":"crossref","first-page":"107705","DOI":"10.1016\/j.isci.2023.107705","article-title":"SARS-CoV-2 Nsp15 suppresses type I interferon production by inhibiting IRF3 phosphorylation and nuclear translocation","volume":"26","author":"D Zhang","year":"2023","journal-title":"iScience"},{"issue":"5","key":"ppat.1012571.ref015","doi-asserted-by":"crossref","first-page":"e5466","DOI":"10.1371\/journal.pone.0005466","article-title":"MAVS-mediated apoptosis and its inhibition by viral proteins","volume":"4","author":"Y Lei","year":"2009","journal-title":"PLoS One"},{"issue":"7","key":"ppat.1012571.ref016","doi-asserted-by":"crossref","first-page":"109126","DOI":"10.1016\/j.celrep.2021.109126","article-title":"Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities","volume":"35","author":"M Hayn","year":"2021","journal-title":"Cell Rep"},{"issue":"8","key":"ppat.1012571.ref017","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.1128\/JVI.07012-11","article-title":"The coronavirus endoribonuclease nsp15 interacts with retinoblastoma tumor suppressor protein","volume":"86","author":"K Bhardwaj","year":"2012","journal-title":"J Virol"},{"issue":"2","key":"ppat.1012571.ref018","doi-asserted-by":"crossref","first-page":"e1008690","DOI":"10.1371\/journal.ppat.1008690","article-title":"Inhibition of anti-viral stress granule formation by coronavirus endoribonuclease nsp15 ensures efficient virus replication","volume":"17","author":"B Gao","year":"2021","journal-title":"PLoS Pathog"},{"issue":"12","key":"ppat.1012571.ref019","doi-asserted-by":"crossref","first-page":"e0068622","DOI":"10.1128\/jvi.00686-22","article-title":"Role of stress granules in suppressing viral replication by the infectious bronchitis virus endoribonuclease","volume":"96","author":"J Zhao","year":"2022","journal-title":"J Virol"},{"issue":"12","key":"ppat.1012571.ref020","doi-asserted-by":"crossref","first-page":"e1011041","DOI":"10.1371\/journal.ppat.1011041","article-title":"Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation","volume":"18","author":"SM Dolliver","year":"2022","journal-title":"PLoS Pathog"},{"issue":"8","key":"ppat.1012571.ref021","doi-asserted-by":"crossref","first-page":"e02000-18","DOI":"10.1128\/JVI.02000-18","article-title":"Coronavirus endoribonuclease activity in porcine epidemic diarrhea virus suppresses type I and type III interferon responses","volume":"93","author":"X Deng","year":"2019","journal-title":"J Virol"},{"issue":"21","key":"ppat.1012571.ref022","doi-asserted-by":"crossref","first-page":"e2123208119","DOI":"10.1073\/pnas.2123208119","article-title":"MERS-CoV endoribonuclease and accessory proteins jointly evade host innate immunity during infection of lung and nasal epithelial cells","volume":"119","author":"CE Comar","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"15","key":"ppat.1012571.ref023","doi-asserted-by":"crossref","first-page":"e2320194121","DOI":"10.1073\/pnas.2320194121","article-title":"SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling","volume":"121","author":"CJ Otter","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"ppat.1012571.ref024","doi-asserted-by":"crossref","first-page":"e0220923","DOI":"10.1128\/spectrum.02209-23","article-title":"Diversity for endoribonuclease nsp15-mediated regulation of alpha-coronavirus propagation and virulence","volume":"11","author":"Y Xie","year":"2023","journal-title":"Microbiol Spectr"},{"key":"ppat.1012571.ref025","article-title":"SARS-CoV-2 EndoU-ribonuclease regulates RNA recombination and impacts viral fitness","author":"Y Zhou","year":"2024.","journal-title":"bioRxiv: the Preprint Server for Biology"},{"key":"ppat.1012571.ref026","article-title":"SARS-CoV-2 Nsp15 antagonizes the cGAS-STING-mediated antiviral innate immune responses","author":"HP Chiu","year":"2024","journal-title":"bioRxiv: the Preprint Server for Biology"},{"key":"ppat.1012571.ref027","first-page":"125","article-title":"Small molecule inhibitors of the SARS-CoV nsp15 endoribonuclease","volume":"2","author":"JM Ortiz-Alcantara","year":"2010","journal-title":"Virus Adapt Treat"},{"issue":"13","key":"ppat.1012571.ref028","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1042\/BCJ20210199","article-title":"Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp15 endoribonuclease","volume":"478","author":"B Canal","year":"2021","journal-title":"Biochem J"},{"issue":"4","key":"ppat.1012571.ref029","doi-asserted-by":"crossref","first-page":"e0250019","DOI":"10.1371\/journal.pone.0250019","article-title":"High-throughput screening of the ReFRAME, Pandemic Box, and COVID Box drug repurposing libraries against SARS-CoV-2 nsp15 endoribonuclease to identify small-molecule inhibitors of viral activity","volume":"16","author":"R Choi","year":"2021","journal-title":"PLoS One"},{"issue":"21","key":"ppat.1012571.ref030","doi-asserted-by":"crossref","first-page":"5948","DOI":"10.1021\/acs.jafc.1c02050","article-title":"Epigallocatechin gallate inhibits the uridylate-specific endoribonuclease nsp15 and efficiently neutralizes the SARS-CoV-2 strain","volume":"69","author":"S Hong","year":"2021","journal-title":"J Agric Food Chem"},{"issue":"11","key":"ppat.1012571.ref031","doi-asserted-by":"crossref","first-page":"105341","DOI":"10.1016\/j.jbc.2023.105341","article-title":"Reversible and irreversible inhibitors of coronavirus Nsp15 endoribonuclease","volume":"299","author":"J Chen","year":"2023","journal-title":"J Biol Chem"},{"key":"ppat.1012571.ref032","doi-asserted-by":"crossref","first-page":"896504","DOI":"10.3389\/fcimb.2022.896504","article-title":"Antibiotic-induced primary biles inhibit SARS-CoV-2 endoribonuclease nsp15 activity in mouse gut","volume":"12","author":"Y Ma","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"ppat.1012571.ref033","doi-asserted-by":"crossref","first-page":"116886","DOI":"10.1016\/j.ejmech.2024.116886","article-title":"Exploration of isatin-based inhibitors of SARS-CoV-2 Nsp15 endoribonuclease","volume":"279","author":"T Rampias","year":"2024","journal-title":"Eur J Med Chem"},{"issue":"1","key":"ppat.1012571.ref034","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s42003-021-01735-9","article-title":"Tipiracil binds to uridine site and inhibits nsp15 endoribonuclease NendoU from SARS-CoV-2","volume":"4","author":"Y Kim","year":"2021","journal-title":"Commun Biol"},{"issue":"1","key":"ppat.1012571.ref035","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1038\/s41467-020-20608-z","article-title":"Cryo-EM structures of the SARS-CoV-2 endoribonuclease nsp15 reveal insight into nuclease specificity and dynamics","volume":"12","author":"MC Pillon","year":"2021","journal-title":"Nat Commun"},{"issue":"17","key":"ppat.1012571.ref036","doi-asserted-by":"crossref","first-page":"10136","DOI":"10.1093\/nar\/gkab719","article-title":"Characterization of SARS2 nsp15 nuclease activity reveals it\u2019s mad about U","volume":"49","author":"MN Frazier","year":"2021","journal-title":"Nucleic Acids Res"},{"issue":"14","key":"ppat.1012571.ref037","doi-asserted-by":"crossref","first-page":"8290","DOI":"10.1093\/nar\/gkac589","article-title":"Flipped over U: structural basis for dsRNA cleavage by the SARS-CoV-2 endoribonuclease","volume":"50","author":"MN Frazier","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"ppat.1012571.ref038","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1093\/procel\/pwae009","article-title":"Structural basis for polyuridine tract recognition by SARS-CoV-2 Nsp15","volume":"15","author":"F Ito","year":"2024","journal-title":"Protein Cell"},{"issue":"32","key":"ppat.1012571.ref039","doi-asserted-by":"crossref","first-page":"11892","DOI":"10.1073\/pnas.0601708103","article-title":"Crystal structure and mechanistic determinants of SARS coronavirus nonstructural protein 15 define an endoribonuclease family","volume":"103","author":"S Ricagno","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"issue":"12","key":"ppat.1012571.ref040","doi-asserted-by":"crossref","first-page":"6700","DOI":"10.1128\/JVI.02817-06","article-title":"Crystal structure of a monomeric form of severe acute respiratory syndrome coronavirus endonuclease nsp15 suggests a role for hexamerization as an allosteric switch","volume":"81","author":"JS Joseph","year":"2007","journal-title":"J Virol"},{"key":"ppat.1012571.ref041","doi-asserted-by":"crossref","first-page":"105921","DOI":"10.1016\/j.antiviral.2024.105921","article-title":"The coronavirus nsp15 endoribonuclease: A puzzling protein and pertinent antiviral drug target","volume":"228","author":"B Van Loy","year":"2024","journal-title":"Antiviral Res"},{"issue":"9","key":"ppat.1012571.ref042","doi-asserted-by":"crossref","first-page":"5632","DOI":"10.1021\/acs.jmedchem.0c02124","article-title":"Betulonic acid derivatives interfering with human coronavirus 229E replication via the nsp15 endoribonuclease","volume":"64","author":"A Stevaert","year":"2021","journal-title":"J Med Chem"},{"issue":"2","key":"ppat.1012571.ref043","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/nbt.3437","article-title":"Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9","volume":"34","author":"JG Doench","year":"2016","journal-title":"Nat Biotechnol"},{"issue":"4","key":"ppat.1012571.ref044","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/j.cell.2018.09.022","article-title":"Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens","volume":"175","author":"A Wroblewska","year":"2018","journal-title":"Cell"},{"issue":"4","key":"ppat.1012571.ref045","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1099\/jgv.0.001235","article-title":"Influenza virus entry via the GM3 ganglioside-mediated platelet-derived growth factor receptor beta signalling pathway","volume":"100","author":"P Vrijens","year":"2019","journal-title":"J Gen Virol"},{"issue":"7","key":"ppat.1012571.ref046","doi-asserted-by":"crossref","first-page":"139","DOI":"10.3390\/ph13070139","article-title":"Reprogramming of the antibacterial drug vancomycin results in potent antiviral agents devoid of antibacterial activity","volume":"13","author":"Z Sz\u0171cs","year":"2020","journal-title":"Pharmaceuticals (Basel)"},{"issue":"4","key":"ppat.1012571.ref047","doi-asserted-by":"crossref","first-page":"e1009500","DOI":"10.1371\/journal.ppat.1009500","article-title":"The SARS-CoV-2 and other human coronavirus spike proteins are fine-tuned towards temperature and proteases of the human airways","volume":"17","author":"M Laporte","year":"2021","journal-title":"PLoS Pathog"},{"issue":"8","key":"ppat.1012571.ref048","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.3390\/ph15081021","article-title":"A versatile class of 1,4,4-trisubstituted piperidines block coronavirus replication in vitro","volume":"15","author":"S De Castro","year":"2022","journal-title":"Pharmaceuticals (Basel)"},{"issue":"10","key":"ppat.1012571.ref049","doi-asserted-by":"crossref","first-page":"2770","DOI":"10.1093\/jac\/dku209","article-title":"Mutations in the chikungunya virus non-structural proteins cause resistance to favipiravir (T-705), a broad-spectrum antiviral","volume":"69","author":"L Delang","year":"2014","journal-title":"J Antimicrob Chemother"},{"issue":"3","key":"ppat.1012571.ref050","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1038\/s41596-021-00491-8","article-title":"Engineering SARS-CoV-2 using a reverse genetic system","volume":"16","author":"X Xie","year":"2021","journal-title":"Nat Protoc"},{"issue":"23","key":"ppat.1012571.ref051","doi-asserted-by":"crossref","first-page":"4572","DOI":"10.1093\/bioinformatics\/btab705","article-title":"New strategies to improve minimap2 alignment accuracy","volume":"37","author":"H Li","year":"2021","journal-title":"Bioinformatics"},{"issue":"69","key":"ppat.1012571.ref052","doi-asserted-by":"crossref","first-page":"3722","DOI":"10.21105\/joss.03722","article-title":"Bam-readcount - rapid generation of basepair-resolution sequence metrics","volume":"7","author":"A Khanna","year":"2022","journal-title":"Journal of Open Source Software"},{"issue":"16","key":"ppat.1012571.ref053","doi-asserted-by":"crossref","first-page":"7909","DOI":"10.1128\/JVI.00525-06","article-title":"New antiviral target revealed by the hexameric structure of mouse hepatitis virus nonstructural protein nsp15","volume":"80","author":"X Xu","year":"2006","journal-title":"J Virol"},{"issue":"5","key":"ppat.1012571.ref054","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.jmb.2005.09.007","article-title":"Mutational analysis of the SARS virus nsp15 endoribonuclease: identification of residues affecting hexamer formation","volume":"353","author":"LA Guarino","year":"2005","journal-title":"J Mol Biol"},{"issue":"3","key":"ppat.1012571.ref055","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.gpb.2022.01.004","article-title":"SynergyFinder Plus: Toward better interpretation and annotation of drug combination screening datasets","volume":"20","author":"S Zheng","year":"2022","journal-title":"Genomics Proteomics Bioinformatics"},{"issue":"1","key":"ppat.1012571.ref056","doi-asserted-by":"crossref","first-page":"e01387","DOI":"10.1128\/JVI.01387-16","article-title":"Clinical isolates of human coronavirus 229E bypass the endosome for cell entry","volume":"91","author":"K Shirato","year":"2017","journal-title":"J Virol"},{"issue":"5","key":"ppat.1012571.ref057","doi-asserted-by":"crossref","first-page":"e1004166","DOI":"10.1371\/journal.ppat.1004166","article-title":"Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the Middle East respiratory syndrome virus","volume":"10","author":"A Lundin","year":"2014","journal-title":"PLoS Pathog"},{"issue":"2","key":"ppat.1012571.ref058","doi-asserted-by":"crossref","first-page":"256","DOI":"10.3390\/v16020256","article-title":"The main protease of Middle East respiratory syndrome coronavirus induces cleavage of mitochondrial antiviral signaling protein to antagonize the innate immune response","volume":"16","author":"M van Huizen","year":"2024","journal-title":"Viruses"},{"issue":"5","key":"ppat.1012571.ref059","doi-asserted-by":"crossref","first-page":"e0233521","DOI":"10.1128\/mBio.02335-21","article-title":"SARS-CoV-2 Nsp5 demonstrates two distinct mechanisms targeting RIG-I and MAVS to evade the innate immune response","volume":"12","author":"Y Liu","year":"2021","journal-title":"mBio"},{"key":"ppat.1012571.ref060","doi-asserted-by":"crossref","first-page":"1251705","DOI":"10.3389\/fmicb.2023.1251705","article-title":"Characterization of host substrates of SARS-CoV-2 main protease","volume":"14","author":"I Melano","year":"2023","journal-title":"Front Microbiol"},{"issue":"3","key":"ppat.1012571.ref061","doi-asserted-by":"crossref","first-page":"102990","DOI":"10.1016\/j.jbc.2023.102990","article-title":"The main protease of SARS-CoV-2 cleaves histone deacetylases and DCP1A, attenuating the immune defense of the interferon-stimulated genes","volume":"299","author":"L Song","year":"2023","journal-title":"J Biol Chem"},{"issue":"6","key":"ppat.1012571.ref062","doi-asserted-by":"crossref","first-page":"599","DOI":"10.3390\/v12060599","article-title":"Porcine epidemic diarrhea virus nsp15 antagonizes interferon signaling by RNA degradation of TBK1 and IRF3","volume":"12","author":"Y Wu","year":"2020","journal-title":"Viruses"},{"issue":"3","key":"ppat.1012571.ref063","doi-asserted-by":"crossref","first-page":"e3001158","DOI":"10.1371\/journal.pbio.3001158","article-title":"Disparate temperature-dependent virus-host dynamics for SARS-CoV-2 and SARS-CoV in the human respiratory epithelium","volume":"19","author":"P V\u2019Kovski","year":"2021","journal-title":"PLoS Biol"},{"issue":"3","key":"ppat.1012571.ref064","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1073\/pnas.1411030112","article-title":"Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells","volume":"112","author":"EF Foxman","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"ppat.1012571.ref065","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nchembio.318","article-title":"Turning enzymes ON with small molecules","volume":"6","author":"JA Zorn","year":"2010","journal-title":"Nat Chem Biol"},{"issue":"6","key":"ppat.1012571.ref066","doi-asserted-by":"crossref","first-page":"104787","DOI":"10.1016\/j.jbc.2023.104787","article-title":"Kinetic analysis of RNA cleavage by coronavirus nsp15 endonuclease: evidence for acid-base catalysis and substrate-dependent metal ion activation","volume":"299","author":"T Huang","year":"2023","journal-title":"J Biol Chem"},{"issue":"22","key":"ppat.1012571.ref067","doi-asserted-by":"crossref","first-page":"12218","DOI":"10.1128\/JVI.78.22.12218-12224.2004","article-title":"The severe acute respiratory syndrome coronavirus Nsp15 protein is an endoribonuclease that prefers manganese as a cofactor","volume":"78","author":"K Bhardwaj","year":"2004","journal-title":"J Virol"},{"issue":"24","key":"ppat.1012571.ref068","doi-asserted-by":"crossref","first-page":"13587","DOI":"10.1128\/JVI.00547-07","article-title":"Biochemical and genetic analyses of murine hepatitis virus nsp15 endoribonuclease","volume":"81","author":"H Kang","year":"2007","journal-title":"J Virol"},{"issue":"13","key":"ppat.1012571.ref069","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera - a visualization system for exploratory research and analysis","volume":"25","author":"EF Pettersen","year":"2004","journal-title":"J Comput Chem"},{"issue":"Web Server issue","key":"ppat.1012571.ref070","doi-asserted-by":"crossref","first-page":"W320","DOI":"10.1093\/nar\/gku316","article-title":"Deciphering key features in protein structures with the new ENDscript server","volume":"42","author":"X Robert","year":"2014","journal-title":"Nucleic Acids Res"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1012571","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012571","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T13:57:18Z","timestamp":1740491838000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1012571"}},"subtitle":[],"editor":[{"given":"Craig","family":"McCormick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,2,11]]},"references-count":70,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1012571","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.09.09.611961","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,11]]}}}