{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:11:43Z","timestamp":1792624303738,"version":"4.5.0"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2004,10,1]],"date-time":"2004-10-01T00:00:00Z","timestamp":1096588800000},"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":[[2004,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-adenosine and 2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5\u2032-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and\/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg\/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.\n          <\/jats:p>","DOI":"10.1128\/aac.48.10.3944-3953.2004","type":"journal-article","created":{"date-parts":[[2004,9,23]],"date-time":"2004-09-23T19:02:50Z","timestamp":1095966170000},"page":"3944-3953","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":220,"title":["A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties"],"prefix":"10.1128","volume":"48","author":[{"given":"David B.","family":"Olsen","sequence":"first","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne B.","family":"Eldrup","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Isis Pharmaceuticals, Carlsbad, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Bartholomew","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balkrishen","family":"Bhat","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Isis Pharmaceuticals, Carlsbad, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele R.","family":"Bosserman","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Ceccacci","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence F.","family":"Colwell","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Fay","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osvaldo A.","family":"Flores","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista L.","family":"Getty","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay A.","family":"Grobler","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"LaFemina","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Markel","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Migliaccio","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marija","family":"Prhavc","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Isis Pharmaceuticals, Carlsbad, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W.","family":"Stahlhut","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne E.","family":"Tomassini","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm","family":"MacCoss","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria J.","family":"Hazuda","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven S.","family":"Carroll","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Merck Research Laboratories, West Point, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1107\/S0567740873003195","volume":"29","year":"1973","unstructured":"Abola, J., and M. 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