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Here, we expand our studies on \u03b2-\n            <jats:sc>d<\/jats:sc>\n            -2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-2,6-diaminopurine-ribonucleotide (DAPN) phosphoramidate prodrug 1 (PD1) as a novel investigational inhibitor of HCV. DAPN-PD1 is metabolized intracellularly into two distinct bioactive nucleoside triphosphate (TP) analogs. The first metabolite, 2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-GTP, is a well-characterized inhibitor of NS5B polymerase, whereas the second metabolite, 2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-DAPN-TP, behaves as an adenosine base analog.\n            <jats:italic>In vitro<\/jats:italic>\n            assays suggest that both metabolites are inhibitors of NS5B-mediated RNA polymerization. Additional factors, such as rNAI-TP incorporation efficiencies, intracellular rNAI-TP levels, and competition with natural ribonucleotides, were examined in order to further characterize the potential role of each nucleotide metabolite\n            <jats:italic>in vivo<\/jats:italic>\n            . Finally, we found that although both 2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-GTP and 2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-DAPN-TP were weak substrates for human mitochondrial RNA (mtRNA) polymerase (POLRMT)\n            <jats:italic>in vitro<\/jats:italic>\n            , DAPN-PD1 did not cause off-target inhibition of mtRNA transcription in Huh-7 cells. In contrast, administration of BMS-986094, which also generates 2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-GTP and previously has been associated with toxicity in humans, caused detectable inhibition of mtRNA transcription. Metabolism of BMS-986094 in Huh-7 cells leads to 87-fold higher levels of intracellular 2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -methyl-GTP than DAPN-PD1. Collectively, our data characterize DAPN-PD1 as a novel and potent antiviral agent that combines the delivery of two active metabolites.\n          <\/jats:p>","DOI":"10.1128\/aac.00318-16","type":"journal-article","created":{"date-parts":[[2016,5,24]],"date-time":"2016-05-24T16:26:28Z","timestamp":1464107188000},"page":"4659-4669","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["Biochemical Characterization of the Active Anti-Hepatitis C Virus Metabolites of 2,6-Diaminopurine Ribonucleoside Prodrug Compared to Sofosbuvir and BMS-986094"],"prefix":"10.1128","volume":"60","author":[{"given":"Maryam","family":"Ehteshami","sequence":"first","affiliation":[{"name":"Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, 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