{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T03:31:20Z","timestamp":1772767880679,"version":"3.50.1"},"reference-count":21,"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            Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen that infects humans. Neither a vaccine nor an antiviral therapy is currently available for DENV. Here, we report an adenosine nucleoside prodrug that potently inhibits DENV replication both in cell culture and in a DENV mouse model. NITD449 (2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -acetylene-7-deaza-7-carbamoyladenosine) was initially identified as a parental compound that inhibits all four serotypes of DENV with low cytotoxicity. However,\n            <jats:italic>in vivo<\/jats:italic>\n            pharmacokinetic studies indicated that NITD449 had a low level of exposure in plasma when dosed orally. To increase the oral bioavailability, we covalently linked isobutyric acids to the 3\u2032- and 5\u2032-hydroxyl groups of ribose via ester linkage to NITD449, leading to the prodrug NITD203 (3\u2032,5\u2032-\n            <jats:italic>O<\/jats:italic>\n            -diisobutyryl-2\u2032-\n            <jats:italic>C<\/jats:italic>\n            -acetylene-7-deaza-7-carbamoyl-adenosin). Pharmacokinetic analysis showed that upon oral dosing of the prodrug, NITD203 was readily converted to NITD449, resulting in improved exposure of the parental compound in plasma in both mouse and rat. In DENV-infected AG129 mice, oral dosing of the prodrug at 25 mg\/kg of body weight reduced peak viremia by 30-fold. Antiviral spectrum analysis showed that NITD203 inhibited various flaviviruses (DENV, yellow fever virus, and West Nile virus) and hepatitis C virus but not Chikungunya virus (an alphavirus). Mode-of-action analysis, using a luciferase-reporting replicon, indicated that NITD203 inhibited DENV RNA synthesis. Although NITD203 exhibited potent\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            efficacies, the compound could not reach a satisfactory no-observable-adverse-effect level (NOAEL) in a 2-week\n            <jats:italic>in vivo<\/jats:italic>\n            toxicity study. Nevertheless, our results demonstrate that a prodrug approach using a nucleoside analog could potentially be developed for flavivirus antiviral therapy.\n          <\/jats:p>","DOI":"10.1128\/aac.00397-10","type":"journal-article","created":{"date-parts":[[2010,6,2]],"date-time":"2010-06-02T01:10:43Z","timestamp":1275441043000},"page":"3255-3261","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":49,"title":["Inhibition of Dengue Virus by an Ester Prodrug of an Adenosine Analog"],"prefix":"10.1128","volume":"54","author":[{"given":"Yen-Liang","family":"Chen","sequence":"first","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Yin","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"},{"name":"College of Pharmacy &amp; State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suresh B.","family":"Lakshminarayana","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Qing","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wouter","family":"Schul","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeyaraj","family":"Duraiswamy","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ravinder Reddi","family":"Kondreddi","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Goh","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao Ying","family":"Xu","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andy","family":"Yip","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boping","family":"Liu","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret","family":"Weaver","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronique","family":"Dartois","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas H.","family":"Keller","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei-Yong","family":"Shi","sequence":"additional","affiliation":[{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"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":"10.1128\/AAC.00140-10"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa012035"},{"key":"e_1_3_2_5_2","first-page":"53","volume":"2009","year":"2009","unstructured":"De Clercq, E., and J. 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