{"doi":"10.1128/jvi.02064-13","title":"The Viral Polymerase Inhibitor 2′-\n            <i>C</i>\n            -Methylcytidine Inhibits Norwalk Virus Replication and Protects against Norovirus-Induced Diarrhea and Mortality in a Mouse Model","abstract":"<jats:title>ABSTRACT</jats:title>\n          <jats:p>\n            Human noroviruses are a major cause of food-borne illness, accountable for 50% of all-etiologies outbreaks of acute gastroenteritis (in both developing and developed countries). There is no vaccine or antiviral drug for the prophylaxis or treatment of norovirus-induced gastroenteritis. We recently reported the inhibitory effect of 2′-\n            <jats:italic>C</jats:italic>\n            -methylcytidine (2CMC), a hepatitis C virus polymerase inhibitor, on the\n            <jats:italic>in vitro</jats:italic>\n            replication of murine norovirus (MNV). Here we evaluated the inhibitory effect of 2CMC on\n            <jats:italic>in vitro</jats:italic>\n            human norovirus replication through a Norwalk virus replicon model and in a mouse model by using AG129 mice orally infected with MNV. Survival, weight, and fecal consistency were monitored, and viral loads in stool samples and organs were quantified. Intestines were examined histologically. 2CMC reduced Norwalk virus replicon replication in a dose-dependent manner and was able to clear cells of the replicon. Treatment of MNV-infected AG129 mice with 2CMC (i) prevented norovirus-induced diarrhea; (ii) markedly delayed the appearance of viral RNA and reduced viral RNA titers in the intestine, mesenteric lymph nodes, spleen, lungs, and stool; (iii) completely prevented virus-induced mortality; and (iv) resulted in protective immunity against a rechallenge. We demonstrate for the first time that a small-molecule inhibitor of norovirus replication protects from virus-induced disease and mortality in a relevant animal model. These findings pave the way for the development of potent and safe antivirals as prophylaxis and therapy of norovirus infection.\n          </jats:p>","journal":"Journal of Virology","year":2013,"id":16893,"datarank":3.4779388107338267,"base_score":4.584967478670572,"endowment":4.584967478670572,"self_citation_contribution":0.687745121800586,"citation_network_contribution":2.7901936889332406,"self_endowment_contribution":0.687745121800586,"citer_contribution":2.7901936889332406,"corpus_percentile":null,"corpus_rank":null,"citation_count":97,"citer_count":72,"citers_with_citation_signal":65,"citers_with_endowment":65,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":122900,"name":"Dirk Jochmans","orcid":null,"position":1,"is_corresponding":false},{"id":122901,"name":"Yannick Debing","orcid":null,"position":2,"is_corresponding":false},{"id":122902,"name":"Erik Verbeken","orcid":null,"position":3,"is_corresponding":false},{"id":122903,"name":"Maria S. J. Nascimento","orcid":null,"position":4,"is_corresponding":false},{"id":122904,"name":"Johan Neyts","orcid":null,"position":5,"is_corresponding":false},{"id":122899,"name":"Joana Rocha-Pereira","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":4.584967478670572,"endowment":4.584967478670572,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23986582","pmcid":"PMC3807313","openalex_id":"https://openalex.org/W2085056532","authors":[],"funders":[{"funder_name":"European Commission","grant_id":"260644","title":"Small-molecule Inhibitor Leads Versus emerging and neglected RNA viruses"}],"total_grants":1,"fwci":6.4787,"citation_percentile":0.97458631,"influential_citations":3,"citation_trend":[{"year":2013,"count":1},{"year":2014,"count":10},{"year":2015,"count":12},{"year":2016,"count":14},{"year":2017,"count":7},{"year":2018,"count":9},{"year":2019,"count":14},{"year":2020,"count":2},{"year":2021,"count":8},{"year":2022,"count":5},{"year":2023,"count":4},{"year":2024,"count":6},{"year":2025,"count":5}],"oa_status":"bronze","license":"ASM Journals Non-Commercial TDM","oa_locations":[{"url":"https://jvi.asm.org/content/jvi/87/21/11798.full.pdf","host_type":"journal"},{"url":"https://jvi.asm.org/content/jvi/87/21/11798.full.pdf","host_type":"BRONZE"},{"url":"https://jvi.asm.org/content/jvi/87/21/11798.full.pdf","host_type":"publisher"},{"url":"https://journals.asm.org/doi/pdf/10.1128/JVI.02064-13","host_type":"publisher"},{"url":"https://doi.org/10.1128/jvi.02064-13","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/23986582","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3807313","host_type":"repository"},{"url":"http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=23986582","host_type":"repository"},{"url":"http://dx.doi.org/10.1128/JVI.02064-13","host_type":""},{"url":"https://dx.doi.org/10.1128/jvi.02064-13","host_type":""},{"url":"https://lirias.kuleuven.be/handle/123456789/418946","host_type":""}],"fields_of_study":["Viral gastroenteritis research and epidemiology","Viral Infections and Immunology Research","Animal Virus Infections Studies","Medicine","Biology","0301 basic medicine","03 medical and health sciences","0303 health sciences","Animal Structures","Animals","Antiviral Agents","Body Weight","Caliciviridae Infections","Cytidine","Diarrhea","Disease Models, Animal","Feces","Female","Male","Mice","Norovirus","Norwalk virus","RNA, Viral","Survival Analysis","Viral Load","Virus Replication"],"mesh_terms":["Animals","Animal Structures","Antiviral Agents","Body Weight","Cytidine","Diarrhea","Disease Models, Animal","Feces","Female","Male","Norwalk virus","RNA, Viral","Virus Replication","Survival Analysis","Caliciviridae Infections","Viral Load","Norovirus","Mice"],"keywords":["Norovirus","Virology","Biology","Norwalk virus","Replicon","Murine norovirus","Virus","Viral replication","Caliciviridae","Virus quantification","Diarrhea","Viral load","Microbiology","Medicine","Male","VACCINE","Cytidine","IMMUNITY","Virus Replication","Antiviral Agents","30 Agricultural, veterinary and food sciences","Feces","Mice","07 Agricultural and Veterinary Sciences","INFECTION","Animals","11 Medical and Health Sciences","Caliciviridae Infections","Science & Technology","GASTROENTERITIS","31 Biological sciences","Body Weight","VALOPICITABINE NM283","Animal Structures","32 Biomedical and clinical sciences","06 Biological Sciences","Survival Analysis","INTERFERON/RIBAVIRIN PEGIFN/RBV RETREATMENT","Disease Models, Animal","PRIOR NONRESPONSE","RNA, Viral","Female","PEGINTERFERON","Life Sciences & Biomedicine"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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