{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:50:50Z","timestamp":1791172250411,"version":"4.1.0"},"reference-count":61,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2010,8,1]],"date-time":"2010-08-01T00:00:00Z","timestamp":1280620800000},"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":[[2010,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The hepatitis C virus (HCV) NS5B RNA polymerase facilitates the RNA synthesis step during the HCV replication cycle. Nucleoside analogs targeting the NS5B provide an attractive approach to treating HCV infections because of their high barrier to resistance and pan-genotype activity. PSI-7851, a pronucleotide of \u03b2-\n            <jats:sc>d<\/jats:sc>\n            -2\u2032-deoxy-2\u2032-fluoro-2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyluridine-5\u2032-monophosphate, is a highly active nucleotide analog inhibitor of HCV for which a phase 1b multiple ascending dose study of genotype 1-infected individuals was recently completed (M. Rodriguez-Torres, E. Lawitz, S. Flach, J. M. Denning, E. Albanis, W. T. Symonds, and M. M. Berry, Abstr. 60th Annu. Meet. Am. Assoc. Study Liver Dis., abstr. LB17, 2009). The studies described here characterize the\n            <jats:italic>in vitro<\/jats:italic>\n            antiviral activity and cytotoxicity profile of PSI-7851. The 50% effective concentration for PSI-7851 against the genotype 1b replicon was determined to be 0.075 \u00b1 0.050 \u03bcM (mean \u00b1 standard deviation). PSI-7851 was similarly effective against replicons derived from genotypes 1a, 1b, and 2a and the genotype 1a and 2a infectious virus systems. The active triphosphate, PSI-7409, inhibited recombinant NS5B polymerases from genotypes 1 to 4 with comparable 50% inhibitory concentrations. PSI-7851 is a specific HCV inhibitor, as it lacks antiviral activity against other closely related and unrelated viruses. PSI-7409 also lacked any significant activity against cellular DNA and RNA polymerases. No cytotoxicity, mitochondrial toxicity, or bone marrow toxicity was associated with PSI-7851 at the highest concentration tested (100 \u03bcM). Cross-resistance studies using replicon mutants conferring resistance to modified nucleoside analogs showed that PSI-7851 was less active against the S282T replicon mutant, whereas cells expressing a replicon containing the S96T\/N142T mutation remained fully susceptible to PSI-7851. Clearance studies using replicon cells demonstrated that PSI-7851 was able to clear cells of HCV replicon RNA and prevent viral rebound.\n          <\/jats:p>","DOI":"10.1128\/aac.00399-10","type":"journal-article","created":{"date-parts":[[2010,6,2]],"date-time":"2010-06-02T01:10:43Z","timestamp":1275441043000},"page":"3187-3196","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":129,"title":["PSI-7851, a Pronucleotide of \u03b2-\n            <scp>d<\/scp>\n            -2\u2032-Deoxy-2\u2032-Fluoro-2\u2032-\n            <i>C<\/i>\n            -Methyluridine Monophosphate, Is a Potent and Pan-Genotype Inhibitor of Hepatitis C Virus Replication"],"prefix":"10.1128","volume":"54","author":[{"given":"Angela M.","family":"Lam","sequence":"first","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eisuke","family":"Murakami","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Espiritu","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly M. Micolochick","family":"Steuer","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congrong","family":"Niu","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meg","family":"Keilman","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Bao","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronique","family":"Zennou","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel","family":"Bourne","sequence":"additional","affiliation":[{"name":"University of Texas Medical Branch, Galveston, Texas 77555"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin G.","family":"Julander","sequence":"additional","affiliation":[{"name":"Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah 84322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Morrey","sequence":"additional","affiliation":[{"name":"Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah 84322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald F.","family":"Smee","sequence":"additional","affiliation":[{"name":"Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, Utah 84322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N.","family":"Frick","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Heck","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanapalan","family":"Nagarathnam","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce S.","family":"Ross","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Sofia","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Otto","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip A.","family":"Furman","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00444-08"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2005.07.002"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2005.03.006"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.66.5.2814-2820.1992"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2005.12.002"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2009.06.011"},{"key":"e_1_3_2_8_2","first-page":"3","volume":"13","year":"2008","unstructured":"Foster, G., and P. 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