{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T01:08:28Z","timestamp":1789348108702,"version":"build-2803163510"},"reference-count":80,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM158458"],"award-info":[{"award-number":["GM158458"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U19 AI1271292"],"award-info":[{"award-number":["U19 AI1271292"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5U01GM152511"],"award-info":[{"award-number":["5U01GM152511"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,9,14]]},"abstract":"<jats:p>\n                    The ongoing emergence and reemergence of RNA viruses from multiple viral families highlights the urgent need for broad\u2010spectrum antiviral therapeutics. To address this issue, a series of 4\u2032\u2010azido fleximer nucleoside analogs were synthesized and evaluated for broad\u2010spectrum antiviral activity against pathogens of epidemic\/pandemic concern. One compound, KAD\u2010039, featuring a 2\u2032, 3\u2032\u2010diisobutyrate\u20105\u2032\u2010ProTide prodrug, exhibited potent antiviral activity across flaviviruses, filoviruses, and coronaviruses, with EC\n                    <jats:sub>50<\/jats:sub>\n                    values ranging from 1 to 10\u2009\u00b5M and minimal cytotoxicity (CC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009&gt;\u200950\u2009\u00b5M). Pharmacokinetic evaluation of KAD\u2010039 demonstrated high plasma stability in dog, monkey, and human plasma, with half\u2010lives ranging from 19.9 to 28\u2009h but exhibited poor stability in human liver microsomes (\n                    <jats:italic>t<\/jats:italic>\n                    <jats:sub>1\/2<\/jats:sub>\n                    \u2009=\u20096.1\u2009min). To help elucidate the mechanism of action of KAD\u2010039 against these viral families, computational molecular docking studies were performed using the expected triphosphate active form within the cap\/GTP\u2010binding pockets of several viral methyltransferases and showed that KAD\u2010039TP docked into all of the viral MTases with similar or higher predicted affinity compared to the natural substrate. In addition, KAD\u2010039TP displayed reduced predicted affinity for the human N7 methyltransferase, suggesting low host toxicity. These results highlight 4\u2032\u2010azido fleximer analogs as promising broad\u2010spectrum antivirals, potentially functioning through viral methyltransferase inhibition, and support further investigation.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70435","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:58:18Z","timestamp":1788235098000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of a 4\u2032\u2010Azido Fleximer Nucleoside Analog With Broad\u2010Spectrum Antiviral Activity Against DENV, EBOV, and Other RNA Viruses"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8889-7941","authenticated-orcid":false,"given":"Kyle A.","family":"Davis","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Maryland Baltimore County  Baltimore Maryland 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