{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T04:29:03Z","timestamp":1727670543289},"reference-count":32,"publisher":"SAGE Publications","issue":"5-6","license":[{"start":{"date-parts":[[2015,12,1]],"date-time":"2015-12-01T00:00:00Z","timestamp":1448928000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antivir Chem Chemother"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p> The novel phenanthridinone derivative HA-719 has recently been identified as a highly potent and selective inhibitor of hepatitis C virus replication. To elucidate its mechanism of inhibition, we have isolated and analyzed a clone of hepatitis C virus replicon cells resistant to HA-719. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p> To isolate HA-719-resistant replicon cells, Huh-7 cells containing subgenomic hepatitis C virus replicons (genotype 1b) with a luciferase reporter (LucNeo#2) were cultured in the presence of G418 and escalating concentrations of HA-719. After several passages, total RNA was extracted from the growing cells, and Huh-7 cells were transfected with the extracted RNA. Limiting dilution of the transfected cells was performed to obtain an HA-719-resistant clone. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> The 50% effective concentration (EC<jats:sub>50<\/jats:sub>) of HA-719 for hepatitis C virus replication was 0.058\u2009\u00b1\u20090.012\u2009\u00b5M in LucNeo#2 cells. The replicon cells capable of growing in the presence of G418 and 3\u2009\u00b5M HA-719 were obtained after 18 passages (72 days). The HA-719-resistant clone LucNeo719R showed 98.3-fold resistant to the compound (EC<jats:sub>50<\/jats:sub>\u2009=\u20095.66\u2009\u00b1\u20090.92\u2009\u00b5M), but the clone had no cross-resistance to telaprevir (NS3 inhibitor), daclatasvir (NS5A inhibitor), and VX-222 (NS5B inhibitor). The sequence analysis for the wild-type and LucNeo719R identified 3, 2 and 7 mutations in NS3\/4\u2009A, NS4B, and NS5A, respectively, but no mutations in NS5B. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> None of the amino acid mutations in the resistant clone corresponds to those reported to confer drug-resistance to current anti-hepatitis C virus agents, suggesting that the target of HA-719 for hepatitis C virus inhibition differs from those of the existing agents. <\/jats:p><\/jats:sec>","DOI":"10.1177\/2040206616663956","type":"journal-article","created":{"date-parts":[[2016,8,9]],"date-time":"2016-08-09T02:03:15Z","timestamp":1470708195000},"page":"148-154","update-policy":"http:\/\/dx.doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative"],"prefix":"10.1177","volume":"24","author":[{"given":"Wataru","family":"Ito","sequence":"first","affiliation":[{"name":"Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaaki","family":"Toyama","sequence":"additional","affiliation":[{"name":"Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mika","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Division of Persistent and Oncogenic Viruses, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Watashi","sequence":"additional","affiliation":[{"name":"Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaji","family":"Wakita","sequence":"additional","affiliation":[{"name":"Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuichi","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Baba","sequence":"additional","affiliation":[{"name":"Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2016,8,19]]},"reference":[{"key":"bibr1-2040206616663956","doi-asserted-by":"publisher","DOI":"10.1007\/s007050050479"},{"key":"bibr2-2040206616663956","first-page":"1326","volume":"18","author":"Liang TJ","year":"1993","journal-title":"Hepatology"},{"key":"bibr3-2040206616663956","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199506013322202"},{"key":"bibr4-2040206616663956","unstructured":"World Health Organization. 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