{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T10:37:56Z","timestamp":1789641476958,"version":"4.0.0"},"reference-count":53,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2015,10,1]],"date-time":"2015-10-01T00:00:00Z","timestamp":1443657600000},"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":[[2015,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The hepatitis C virus (HCV) NS4B protein is an antiviral therapeutic target for which small-molecule inhibitors have not been shown to exhibit\n            <jats:italic>in vivo<\/jats:italic>\n            efficacy. We describe here the\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            antiviral activity of GSK8853, an imidazo[1,2-\n            <jats:italic>a<\/jats:italic>\n            ]pyrimidine inhibitor that binds NS4B protein. GSK8853 was active against multiple HCV genotypes and developed\n            <jats:italic>in vitro<\/jats:italic>\n            resistance mutations in both genotype 1a and genotype 1b replicons localized to the region of NS4B encoding amino acids 94 to 105. A 20-day\n            <jats:italic>in vitro<\/jats:italic>\n            treatment of replicons with GSK8853 resulted in a 2-log drop in replicon RNA levels, with no resistance mutation breakthrough. Chimeric replicons containing NS4B sequences matching known virus isolates showed similar responses to a compound with genotype 1a sequences but altered efficacy with genotype 1b sequences, likely corresponding to the presence of known resistance polymorphs in those isolates.\n            <jats:italic>In vivo<\/jats:italic>\n            efficacy was tested in a humanized-mouse model of HCV infection, and the results showed a 3-log drop in viral RNA loads over a 7-day period. Analysis of the virus remaining at the end of\n            <jats:italic>in vivo<\/jats:italic>\n            treatment revealed resistance mutations encoding amino acid changes that had not been identified by\n            <jats:italic>in vitro<\/jats:italic>\n            studies, including NS4B N56I and N99H. Our findings provide an\n            <jats:italic>in vivo<\/jats:italic>\n            proof of concept for HCV inhibitors targeting NS4B and demonstrate both the promise and potential pitfalls of developing NS4B inhibitors.\n          <\/jats:p>","DOI":"10.1128\/aac.00813-15","type":"journal-article","created":{"date-parts":[[2015,8,11]],"date-time":"2015-08-11T02:20:26Z","timestamp":1439259626000},"page":"6539-6550","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Preclinical Characterization and\n            <i>In Vivo<\/i>\n            Efficacy of GSK8853, a Small-Molecule Inhibitor of the Hepatitis C Virus NS4B Protein"],"prefix":"10.1128","volume":"59","author":[{"given":"Jeffrey J.","family":"Pouliot","sequence":"first","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Thomson","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Xie","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Horton","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Johnson","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Krull","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Mathis","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshio","family":"Morikawa","sequence":"additional","affiliation":[{"name":"PhoenixBio Co. Ltd., Higashi-Hiroshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Parks","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Peterson","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Shimada","sequence":"additional","affiliation":[{"name":"PhoenixBio Co. Ltd., Higashi-Hiroshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Thomas","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Collegeville, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Vamathevan","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Stevenage, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Van Horn","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Collegeville, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiping","family":"Xiong","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Hamatake","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Peat","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Research Triangle Park, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2005.05.003"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020047"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(01)06102-5"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(12)70060-9"},{"key":"e_1_3_3_6_2","volume-title":"Guidelines for the screening, care, and treatment of persons with hepatitis C infection","author":"World Health Organization","year":"2014","unstructured":"World Health Organization. 2014. 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