{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T01:14:51Z","timestamp":1788052491701,"version":"build-2784847793"},"reference-count":43,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100010029","name":"Taishan Scholar Foundation of Shandong Province","doi-asserted-by":"publisher","award":["tsqn202408055"],"award-info":[{"award-number":["tsqn202408055"]}],"id":[{"id":"10.13039\/501100010029","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFE0206500"],"award-info":[{"award-number":["2023YFE0206500"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2308900"],"award-info":[{"award-number":["2023YFC2308900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2024QH546"],"award-info":[{"award-number":["ZR2024QH546"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373727"],"award-info":[{"award-number":["82373727"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82504570"],"award-info":[{"award-number":["82504570"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2026,11]]},"DOI":"10.1016\/j.ejmech.2026.119132","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:21:15Z","timestamp":1784010075000},"page":"119132","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["Dual prodrugs of N4-hydroxycytidine with ProTide and ester modifications as anti-SARS-CoV-2 agents"],"prefix":"10.1016","volume":"318","author":[{"given":"Ye","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoran","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"De Jonghe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Jochmans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Neyts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9232-953X","authenticated-orcid":false,"given":"Dongwei","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"7","key":"10.1016\/j.ejmech.2026.119132_bib1","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.3390\/jcm14072305","article-title":"Management of SARS-CoV-2 infection-clinical practice guidelines of the Polish association of epidemiologists and infectiologists, for 2025","volume":"14","author":"Flisiak","year":"2025","journal-title":"J. Clin. Med."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119132_bib2","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2025.e41980","article-title":"SARS-CoV-2 drug resistance and therapeutic approaches","volume":"11","author":"Batool","year":"2025","journal-title":"Heliyon"},{"issue":"4","key":"10.1016\/j.ejmech.2026.119132_bib3","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.chembiol.2024.03.008","article-title":"SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs","volume":"31","author":"Iketani","year":"2024","journal-title":"Cell Chem. Biol."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119132_bib4","doi-asserted-by":"crossref","first-page":"722","DOI":"10.3390\/v17050722","article-title":"Evolution of antiviral drug resistance in SARS-CoV-2","volume":"17","author":"Dinata","year":"2025","journal-title":"Viruses"},{"issue":"3","key":"10.1016\/j.ejmech.2026.119132_bib5","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s40588-024-00229-6","article-title":"SARS-CoV-2 resistance to small molecule inhibitors","volume":"11","author":"Lopez","year":"2024","journal-title":"Curr. Clin. Microbiol. Rep."},{"issue":"738","key":"10.1016\/j.ejmech.2026.119132_bib6","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.adi0979","article-title":"An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations","volume":"16","author":"Westberg","year":"2024","journal-title":"Sci. Transl. Med."},{"issue":"19","key":"10.1016\/j.ejmech.2026.119132_bib7","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1056\/NEJMoa2509306","article-title":"Ensitrelvir for Covid-19 postexposure prophylaxis in household contacts","volume":"394","author":"Hayden","year":"2026","journal-title":"N. Engl. J. Med."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119132_bib8","doi-asserted-by":"crossref","first-page":"6463","DOI":"10.1038\/s41467-023-42102-y","article-title":"Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir","volume":"14","author":"Jiang","year":"2023","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejmech.2026.119132_bib9","doi-asserted-by":"crossref","first-page":"4385","DOI":"10.1016\/j.csbj.2023.09.001","article-title":"Current understanding of nucleoside analogs inhibiting the SARS-CoV-2 RNA-dependent RNA polymerase","volume":"21","author":"Xu","year":"2023","journal-title":"Comput. Struct. Biotechnol. J."},{"issue":"3","key":"10.1016\/j.ejmech.2026.119132_bib10","doi-asserted-by":"crossref","DOI":"10.1093\/narmme\/ugaf029","article-title":"Mechanism and spectrum of inhibition of viral polymerases by 2'-deoxy-2'-beta-fluoro-4'-azidocytidine or azvudine","volume":"2","author":"Lee","year":"2025","journal-title":"NAR Mol. Med."},{"key":"10.1016\/j.ejmech.2026.119132_bib11","article-title":"Advances in the effectiveness and safety of azvudine treatment: a comprehensive review","volume":"16","author":"Li","year":"2025","journal-title":"Front. Pharmacol."},{"issue":"6","key":"10.1016\/j.ejmech.2026.119132_bib12","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1021\/acsbiomedchemau.2c00039","article-title":"Forodesine and riboprine exhibit strong Anti-SARS-CoV-2 repurposing potential: in silico and in vitro studies","volume":"2","author":"Rabie","year":"2022","journal-title":"ACS Bio Med Chem Au"},{"key":"10.1016\/j.ejmech.2026.119132_bib13","doi-asserted-by":"crossref","DOI":"10.1016\/j.bioorg.2021.105117","article-title":"New quinoline-triazole conjugates: synthesis, and antiviral properties against SARS-CoV-2","volume":"114","author":"Seliem","year":"2021","journal-title":"Bioorg. Chem."},{"key":"10.1016\/j.ejmech.2026.119132_bib14","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2023.115726","article-title":"Natural products as potential lead compounds to develop new antiviral drugs over the past decade","volume":"260","author":"Zhao","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119132_bib15","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2025.117935","article-title":"1,2,4-Oxadiazoles in medicinal chemistry: trends of the last years","volume":"297","author":"Cherkasova","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119132_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2023.115292","article-title":"Potential RNA-dependent RNA polymerase (RdRp) inhibitors as prospective drug candidates for SARS-CoV-2","volume":"252","author":"Bekheit","year":"2023","journal-title":"Eur. J. Med. Chem."},{"issue":"3","key":"10.1016\/j.ejmech.2026.119132_bib17","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1093\/nar\/gkad1194","article-title":"An exonuclease-resistant chain-terminating nucleotide analogue targeting the SARS-CoV-2 replicase complex","volume":"52","author":"Shannon","year":"2024","journal-title":"Nucleic Acids Res."},{"issue":"11","key":"10.1016\/j.ejmech.2026.119132_bib18","doi-asserted-by":"crossref","first-page":"3678","DOI":"10.1016\/j.apsb.2021.10.011","article-title":"Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation via machine learning","volume":"11","author":"Qin","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119132_bib19","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1038\/s41467-026-68304-8","article-title":"Mechanism of SARS-CoV-2 resistance to nucleotide analog-based antivirals","volume":"17","author":"Liu","year":"2026","journal-title":"Nat. Commun."},{"issue":"515","key":"10.1016\/j.ejmech.2026.119132_bib20","doi-asserted-by":"crossref","first-page":"eaax5866","DOI":"10.1126\/scitranslmed.aax5866","article-title":"Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia","volume":"11","author":"Toots","year":"2019","journal-title":"Sci. Transl. Med."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119132_bib21","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/s41392-021-00837-4","article-title":"A novel model of molnupiravir against SARS-CoV-2 replication: accumulated RNA mutations to induce error catastrophe","volume":"6","author":"Zhao","year":"2021","journal-title":"Signal Transduct. Targeted Ther."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119132_bib22","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12985-025-03057-2","article-title":"Viral kinetics in adults with Covid-19 treated with nirmatrelvir-ritonavir or molnupiravir: a population-based, observational cohort study","volume":"23","author":"Prager","year":"2026","journal-title":"Virol. J."},{"key":"10.1016\/j.ejmech.2026.119132_bib23","article-title":"In vivo pharmacokinetic evaluation of molnupiravir in patients with severe chronic kidney disease","volume":"16","author":"Wang","year":"2025","journal-title":"Front. Pharmacol."},{"issue":"22","key":"10.1016\/j.ejmech.2026.119132_bib24","doi-asserted-by":"crossref","first-page":"12031","DOI":"10.1093\/nar\/gkad1002","article-title":"Uridine-cytidine kinase 2 potentiates the mutagenic influence of the antiviral beta-d-N4-hydroxycytidine","volume":"51","author":"Xu","year":"2023","journal-title":"Nucleic Acids Res."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119132_bib25","doi-asserted-by":"crossref","DOI":"10.1111\/cts.13732","article-title":"Mechanism of action, clinical, and translational science","volume":"17","author":"Maas","year":"2024","journal-title":"Clin. Transl. Sci."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119132_bib26","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1039\/D5MD00810G","article-title":"Prodrug strategies in developing antiviral nucleoside analogs","volume":"17","author":"Suresh","year":"2026","journal-title":"RSC Med. Chem."},{"issue":"6","key":"10.1016\/j.ejmech.2026.119132_bib27","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1021\/acs.jmedchem.7b00734","article-title":"The ProTide prodrug technology: from the concept to the clinic","volume":"61","author":"Mehellou","year":"2018","journal-title":"J. Med. Chem."},{"issue":"19","key":"10.1016\/j.ejmech.2026.119132_bib28","doi-asserted-by":"crossref","first-page":"7202","DOI":"10.1021\/jm100863x","article-title":"Discovery of a beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus","volume":"53","author":"Sofia","year":"2010","journal-title":"J. Med. Chem."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119132_bib29","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1021\/acs.jmedchem.6b01594","article-title":"Discovery and synthesis of a phosphoramidate prodrug of a Pyrrolo[2,1-f][triazin-4-amino] adenine C-Nucleoside (GS-5734) for the treatment of ebola and emerging viruses","volume":"60","author":"Siegel","year":"2017","journal-title":"J. Med. Chem."},{"issue":"19","key":"10.1016\/j.ejmech.2026.119132_bib30","doi-asserted-by":"crossref","first-page":"6434","DOI":"10.1021\/acs.joc.5c00240","article-title":"Stereoselective synthesis of nucleotide analog prodrugs (ProTides) via an oxazaphospholidine method","volume":"90","author":"Nakamura","year":"2025","journal-title":"J. Org. Chem."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119132_bib31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3390\/ph17010035","article-title":"Synthesis and antiviral activity of novel beta-D-N4-Hydroxycytidine ester prodrugs as potential compounds for the treatment of SARS-CoV-2 and other human coronaviruses","volume":"17","author":"Darnotuk","year":"2023","journal-title":"Pharmaceuticals"},{"key":"10.1016\/j.ejmech.2026.119132_bib32","doi-asserted-by":"crossref","DOI":"10.1016\/j.bioorg.2023.106527","article-title":"Synthesis and anti-SARS-CoV-2 evaluation of lipid prodrugs of beta-D-N(4)-hydroxycytidine (NHC) and a 3'-fluoro-substituted analogue of NHC","volume":"135","author":"Wen","year":"2023","journal-title":"Bioorg. Chem."},{"key":"10.1016\/j.ejmech.2026.119132_bib33","doi-asserted-by":"crossref","DOI":"10.1016\/j.antiviral.2024.105871","article-title":"New conjugates based on N4-hydroxycytidine with more potent antiviral efficacy in vitro than EIDD-2801 against SARS-CoV-2 and other human coronaviruses","volume":"225","author":"Siniavin","year":"2024","journal-title":"Antivir. Res."},{"key":"10.1016\/j.ejmech.2026.119132_bib34","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2024.116614","article-title":"Lipid-conjugated nucleoside monophosphate and monophosphonate prodrugs: a versatile drug delivery paradigm","volume":"275","author":"Zhang","year":"2024","journal-title":"Eur. J. Med. Chem."},{"issue":"11","key":"10.1016\/j.ejmech.2026.119132_bib35","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1002\/cmdc.200900289","article-title":"Aryloxy phosphoramidate triesters: a technology for delivering monophosphorylated nucleosides and sugars into cells","volume":"4","author":"Mehellou","year":"2009","journal-title":"ChemMedChem"},{"issue":"10","key":"10.1016\/j.ejmech.2026.119132_bib36","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1080\/17460441.2021.1922385","article-title":"An overview of ProTide technology and its implications to drug discovery","volume":"16","author":"Serpi","year":"2021","journal-title":"Expert Opin. Drug Discov."},{"issue":"4","key":"10.1016\/j.ejmech.2026.119132_bib37","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1021\/acsmedchemlett.2c00105","article-title":"Phosphoramidate prodrugs continue to deliver: the journey of Remdesivir (GS-5734) from the liver to peripheral blood mononuclear cells","volume":"13","author":"Yan","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"issue":"9","key":"10.1016\/j.ejmech.2026.119132_bib38","doi-asserted-by":"crossref","first-page":"7470","DOI":"10.1021\/acs.jmedchem.4c00234","article-title":"Differential bioactivation profiles of different GS-441524 prodrugs in cell and mouse models: protide prodrugs with high cell permeability and susceptibility to cathepsin A are more efficient in delivering antiviral active metabolites to the lung","volume":"67","author":"Li","year":"2024","journal-title":"J. Med. Chem."},{"issue":"14","key":"10.1016\/j.ejmech.2026.119132_bib39","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1021\/acs.biochem.4c00176","article-title":"Regiochemical analysis of the ProTide activation mechanism","volume":"63","author":"Glockzin","year":"2024","journal-title":"Biochemistry"},{"issue":"12","key":"10.1016\/j.ejmech.2026.119132_bib40","doi-asserted-by":"crossref","first-page":"10263","DOI":"10.1021\/acs.jmedchem.4c00597","article-title":"Colloidal aggregation confounds cell-based Covid-19 antiviral screens","volume":"67","author":"Glenn","year":"2024","journal-title":"J. Med. Chem."},{"issue":"20","key":"10.1016\/j.ejmech.2026.119132_bib41","doi-asserted-by":"crossref","first-page":"20979","DOI":"10.1021\/acs.jmedchem.5c01610","article-title":"Membrane perturbations and assay interferences by Ivermectin explain its in vitro SARS-CoV-2 antiviral activities and lack of translatability","volume":"68","author":"Eastman","year":"2025","journal-title":"J. Med. Chem."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119132_bib42","doi-asserted-by":"crossref","first-page":"5838","DOI":"10.1038\/s41467-020-19684-y","article-title":"STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters","volume":"11","author":"Boudewijns","year":"2020","journal-title":"Nat. Commun."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119132_bib43","doi-asserted-by":"crossref","first-page":"670","DOI":"10.3390\/ijms26020670","article-title":"Optimization of SARS-CoV-2 M(pro) inhibitors by a structure-based multilevel virtual screening method","volume":"26","author":"Jing","year":"2025","journal-title":"Int. J. Mol. Sci."}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426005775?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426005775?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:15:00Z","timestamp":1788048900000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523426005775"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,11]]},"references-count":43,"alternative-id":["S0223523426005775"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119132","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2026,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Dual prodrugs of N4-hydroxycytidine with ProTide and ester modifications as anti-SARS-CoV-2 agents","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119132","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Published by Elsevier Masson SAS.","name":"copyright","label":"Copyright"}],"article-number":"119132"}}