{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:56:55Z","timestamp":1789646215496,"version":"4.0.0"},"reference-count":29,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2016,12,1]],"date-time":"2016-12-01T00:00:00Z","timestamp":1480550400000},"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":[[2016,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Nucleoside or nucleotide inhibitors are a highly successful class of antivirals due to selectivity, potency, broad coverage, and high barrier to resistance. Nucleosides are the backbone of combination treatments for HIV, hepatitis B virus, and, since the FDA approval of sofosbuvir in 2013, also for hepatitis C virus (HCV). However, many promising nucleotide inhibitors have advanced to clinical trials only to be terminated due to unexpected toxicity. Here we describe the\n            <jats:italic>in vitro<\/jats:italic>\n            pharmacology of compound 1, a monophosphate prodrug of a 2\u2032-ethynyluridine developed for the treatment of HCV. Compound 1 inhibits multiple HCV genotypes\n            <jats:italic>in vitro<\/jats:italic>\n            (50% effective concentration [EC\n            <jats:sub>50<\/jats:sub>\n            ], 0.05 to 0.1 \u03bcM) with a selectivity index of &gt;300 (50% cytotoxic concentration [CC\n            <jats:sub>50<\/jats:sub>\n            ], 30 \u03bcM in MT-4 cells). The active triphosphate metabolite of compound 1, compound 2, does not inhibit human \u03b1, \u03b2, or \u03b3 DNA polymerases but was a substrate for incorporation by the human mitochondrial RNA polymerase (POLRMT). In dog, the oral administration of compound 1 resulted in elevated serum liver enzymes and microscopic changes in the liver. Transmission electron microscopy showed significant mitochondrial swelling and lipid accumulation in hepatocytes. Gene expression analysis revealed dose-proportional gene signature changes linked to loss of hepatic function and increased mitochondrial dysfunction. The potential of\n            <jats:italic>in vivo<\/jats:italic>\n            toxicity through mitochondrial polymerase incorporation by nucleoside analogs has been previously shown. This study shows that even moderate levels of nucleotide analog incorporation by POLRMT increase the risk of\n            <jats:italic>in vivo<\/jats:italic>\n            mitochondrial dysfunction. Based on these results, further development of compound 1 as an anti-HCV compound was terminated.\n          <\/jats:p>","DOI":"10.1128\/aac.01253-16","type":"journal-article","created":{"date-parts":[[2016,9,20]],"date-time":"2016-09-20T01:59:47Z","timestamp":1474336787000},"page":"7077-7085","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Antiviral Nucleotide Incorporation by Recombinant Human Mitochondrial RNA Polymerase Is Predictive of Increased\n            <i>In Vivo<\/i>\n            Mitochondrial Toxicity Risk"],"prefix":"10.1128","volume":"60","author":[{"given":"Martijn","family":"Fenaux","sequence":"first","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Lin","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiaki","family":"Yokokawa","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Sweeney","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Saunders","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Xie","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siew Pheng","family":"Lim","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Uteng","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoko","family":"Uehara","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Warne","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Gang","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Jones","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya","family":"Yendluri","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Emeryville, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Gu","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals, East Hanover, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Mansfield","sequence":"additional","affiliation":[{"name":"Novartis Institute for BioMedical Research, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Boisclair","sequence":"additional","affiliation":[{"name":"Novartis 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Ultrastructural pathology: an introduction to interpretation. Iowa State University Press, Ames, IA."}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01253-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.01253-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:26:59Z","timestamp":1645475219000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.01253-16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12]]},"references-count":29,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2016,12]]}},"alternative-id":["10.1128\/AAC.01253-16"],"URL":"https:\/\/doi.org\/10.1128\/aac.01253-16","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12]]},"assertion":[{"value":"2016-06-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-08-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-11-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}