{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T23:56:09Z","timestamp":1680825369955},"reference-count":40,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2011,8,1]],"date-time":"2011-08-01T00:00:00Z","timestamp":1312156800000},"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":[[2011,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Chronic infection with hepatitis C virus (HCV) is a major global health burden and is associated with an increased risk of liver cirrhosis and hepatocellular carcinoma. Current therapy for HCV infection has limited efficacy, particularly against genotype 1 virus, and is hampered by a range of adverse effects. Therefore, there is a clear unmet medical need for efficacious and safe direct antiviral drugs for use in combination with current treatments to increase cure rates and shorten treatment times. The broad genotypic coverage achievable with nucleosides or nucleotides and the high genetic barrier to resistance of these compounds observed\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            suggest that this class of inhibitors could be a valuable component of future therapeutic regimens. Here, we report the\n            <jats:italic>in vitro<\/jats:italic>\n            inhibitory activity and mode of action of 2\u2032-deoxy-2\u2032-spirocyclopropylcytidine (TMC647078), a novel and potent nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase that causes chain termination of the nascent HCV RNA chain.\n            <jats:italic>In vitro<\/jats:italic>\n            combination studies with a protease inhibitor resulted in additive efficacy in the suppression of HCV RNA replication, highlighting the potential for the combination of these two classes in the treatment of chronic HCV infection. No cytotoxic effects were observed in various cell lines. Biochemical studies indicated that TMC647078 is phosphorylated mainly by deoxycytidine kinase (dCK) without inhibiting the phosphorylation of the natural substrate, and high levels of triphosphate were observed in Huh7 cells and in primary hepatocytes\n            <jats:italic>in vitro<\/jats:italic>\n            . TMC647078 is a potent novel nucleoside inhibitor of HCV replication with a promising\n            <jats:italic>in vitro<\/jats:italic>\n            virology and biology profile.\n          <\/jats:p>","DOI":"10.1128\/aac.00214-11","type":"journal-article","created":{"date-parts":[[2011,5,17]],"date-time":"2011-05-17T04:54:39Z","timestamp":1305608079000},"page":"3812-3820","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Antiviral Activity and Mode of Action of TMC647078, a Novel Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase"],"prefix":"10.1128","volume":"55","author":[{"given":"Jan Martin","family":"Berke","sequence":"first","affiliation":[{"name":"Tibotec-Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leen","family":"Vijgen","sequence":"additional","affiliation":[{"name":"Tibotec-Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Lachau-Durand","sequence":"additional","affiliation":[{"name":"Tibotec-Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan H.","family":"Powdrill","sequence":"additional","affiliation":[{"name":"McGill University, Department of Microbiology and Immunology, Montreal, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svea","family":"Rawe","sequence":"additional","affiliation":[{"name":"McGill University, Department of Microbiology and Immunology, Montreal, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Sjuvarsson","sequence":"additional","affiliation":[{"name":"the Swedish University of Agricultural Sciences, Department of Anatomy, Physiology and Biochemistry, BMC, P.O. 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Box 575, SE 751 23 Uppsala, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"G\u00f6tte","sequence":"additional","affiliation":[{"name":"McGill University, Department of Microbiology and Immunology, Montreal, Canada"},{"name":"McGill University, Department of Biochemistry, Department of Medicine, Montreal, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Els","family":"Fransen","sequence":"additional","affiliation":[{"name":"Tibotec-Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascale","family":"Dehertogh","sequence":"additional","affiliation":[{"name":"Tibotec-Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christel","family":"Van den Eynde","sequence":"additional","affiliation":[{"name":"Tibotec-Virco Virology BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Leclercq","sequence":"additional","affiliation":[{"name":"Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim H. 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