{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T18:12:25Z","timestamp":1770142345869,"version":"3.49.0"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2014,6,1]],"date-time":"2014-06-01T00:00:00Z","timestamp":1401580800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Norovirus (NoV) is the leading cause of acute gastroenteritis worldwide, causing over 200,000 deaths a year. NoV is nonenveloped, with a single-stranded RNA genome, and is primarily transmitted person to person. The viral RNA-dependent RNA polymerase (RdRp) is critical for the production of genomic and subgenomic RNA and is therefore a prime target for antiviral therapies. Using high-throughput screening, nearly 20,000 \u201clead-like\u201d compounds were tested for inhibitory activity against the NoV genogroup II, genotype 4 (GII.4) RdRp. The four most potent hits demonstrated half-maximal inhibitory concentrations (IC\n            <jats:sub>50<\/jats:sub>\n            s) between 5.0 \u03bcM and 9.8 \u03bcM against the target RdRp. Compounds NIC02 and NIC04 revealed a mixed mode of inhibition, while NIC10 and NIC12 were uncompetitive RdRp inhibitors. When examined using enzymes from related viruses, NIC02 demonstrated broad inhibitory activity while NIC04 was the most specific GII.4 RdRp inhibitor. The antiviral activity was examined using available NoV cell culture models; the GI.1 replicon and the infectious GV.1 murine norovirus (MNV). NIC02 and NIC04 inhibited the replication of the GI.1 replicon, with 50% effective concentrations (EC\n            <jats:sub>50<\/jats:sub>\n            s) of 30.1 \u03bcM and 71.1 \u03bcM, respectively, while NIC10 and NIC12 had no observable effect on the NoV GI.1 replicon. In the MNV model, NIC02 reduced plaque numbers, size, and viral RNA levels in a dose-dependent manner (EC\n            <jats:sub>50<\/jats:sub>\n            s between 2.3 \u03bcM and 4.8 \u03bcM). The remaining three compounds also reduced MNV replication, although with higher EC\n            <jats:sub>50<\/jats:sub>\n            s, ranging from 32 \u03bcM to 38 \u03bcM. In summary, we have identified novel nonnucleoside inhibitor scaffolds that will provide a starting framework for the development and future optimization of targeted antivirals against NoV.\n          <\/jats:p>","DOI":"10.1128\/aac.02799-13","type":"journal-article","created":{"date-parts":[[2014,3,18]],"date-time":"2014-03-18T00:49:54Z","timestamp":1395103794000},"page":"3115-3123","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":42,"title":["Nonnucleoside Inhibitors of Norovirus RNA Polymerase: Scaffolds for Rational Drug Design"],"prefix":"10.1128","volume":"58","author":[{"given":"Auda A.","family":"Eltahla","sequence":"first","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun Lee","family":"Lim","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia"},{"name":"Molecular Laboratory, Department of Pathology, Singapore General Hospital, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John-Sebastian","family":"Eden","sequence":"additional","affiliation":[{"name":"Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Biological Sciences and Sydney Medical School, University of Sydney, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew G.","family":"Kelly","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason M.","family":"Mackenzie","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter A.","family":"White","sequence":"additional","affiliation":[{"name":"School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.qco.0000244053.69253.3d"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1408.071114"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/525259"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1207742"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.06712-11"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.4315\/0362-028X.JFP-11-417"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.02198-07"},{"key":"e_1_3_3_9_2","first-page":"841","volume-title":"Fields virology","author":"Green KY","year":"2001","unstructured":"GreenKYChanockRMKapikanAZ. 2001. 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