{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:50:10Z","timestamp":1791175810229,"version":"4.1.0"},"reference-count":30,"publisher":"American Society for Microbiology","issue":"23","license":[{"start":{"date-parts":[[2011,12,1]],"date-time":"2011-12-01T00:00:00Z","timestamp":1322697600000},"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":["J Virol"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            PSI-352938, a cyclic phosphate nucleotide, and PSI-353661, a phosphoramidate nucleotide, are prodrugs of \u03b2-\n            <jats:sc>d<\/jats:sc>\n            -2\u2032-deoxy-2\u2032-\u03b1-fluoro-2\u2032-\u03b2-\n            <jats:italic>C<\/jats:italic>\n            -methylguanosine-5\u2032-monophosphate. Both compounds are metabolized to the same active 5\u2032-triphosphate, PSI-352666, which serves as an alternative substrate inhibitor of the NS5B RNA-dependent RNA polymerase during HCV replication. PSI-352938 and PSI-353661 retained full activity against replicons containing the S282T substitution, which confers resistance to certain 2\u2032-substituted nucleoside\/nucleotide analogs. PSI-352666 was also similarly active against both wild-type and S282T NS5B polymerases. In order to identify mutations that confer resistance to these compounds,\n            <jats:italic>in vitro<\/jats:italic>\n            selection studies were performed using HCV replicon cells. While no resistant genotype 1a or 1b replicons could be selected, cells containing genotype 2a JFH-1 replicons cultured in the presence of PSI-352938 or PSI-353661 developed resistance to both compounds. Sequencing of the NS5B region identified a number of amino acid changes, including S15G, R222Q, C223Y\/H, L320I, and V321I. Phenotypic evaluation of these mutations indicated that single amino acid changes were not sufficient to significantly reduce the activity of PSI-352938 and PSI-353661. Instead, a combination of three amino acid changes, S15G\/C223H\/V321I, was required to confer a high level of resistance. No cross-resistance exists between the 2\u2032-F-2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methylguanosine prodrugs and other classes of HCV inhibitors, including 2\u2032-modified nucleoside\/-tide analogs such as PSI-6130, PSI-7977, INX-08189, and IDX-184. Finally, we determined that in genotype 1b replicons, the C223Y\/H mutation failed to support replication, and although the A15G\/C223H\/V321I triple mutation did confer resistance to PSI-352938 and PSI-353661, this mutant replicated at only about 10% efficiency compared to the wild type.\n          <\/jats:p>","DOI":"10.1128\/jvi.05639-11","type":"journal-article","created":{"date-parts":[[2011,9,29]],"date-time":"2011-09-29T02:09:58Z","timestamp":1317262198000},"page":"12334-12342","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":54,"title":["Hepatitis C Virus Nucleotide Inhibitors PSI-352938 and PSI-353661 Exhibit a Novel Mechanism of Resistance Requiring Multiple Mutations within Replicon RNA"],"prefix":"10.1128","volume":"85","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":"Christine","family":"Espiritu","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini","family":"Bansal","sequence":"additional","affiliation":[{"name":"Pharmasset, Inc., 303A College Road East, Princeton, New Jersey 08540"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly M.","family":"Micolochick Steuer","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":"Michael 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