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One prominent L\u2010nucleoside is telbivudine (LdT), also known as L\u2010thymidine, and is used for the treatment of chronic HBV infections. However, telbivudine, like many other L\u2010nucleosides, is prone to the development of drug resistance due to commonly occurring point mutations. Additionally, for both LdT and its cytidine analogue, antiviral activity has only been reported against HBV. Looking to improve upon this scaffold, a series of novel \u03b2\u2010L\u20102\u2032\u2010deoxyribonucleoside reverse fleximer nucleoside analogues were synthesized, and several were found to exhibit antiviral activity across several viral families including flaviviruses, filoviruses, hepadnaviruses, herpesviruses, polyomaviruses, and togaviruses. The most promising compound, CHK\u201002, exhibited antiviral activity again human polyomavirus 1 (BK virus) in the nanomolar range (&lt;48\u2009nM), low\u2010micromolar activity against HBV (&lt;0.32 \u00b5M), and moderate activity against several other viruses with minimal toxicity. Thus, this showed that L\u2010nucleoside reverse fleximers may have promise as potent, broad\u2010spectrum antiviral therapeutics. The synthesis and antiviral activity results of these novel \u03b2\u2010L\u20102\u2032\u2010deoxyribonucleoside reverse fleximers are reported herein.<\/jats:p>","DOI":"10.1002\/cmdc.202500829","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T10:13:50Z","timestamp":1772964830000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel \u03b2\u2010L\u20102\u2032\u2010deoxyribonucleoside Reverse Fleximers with Inhibitory Activity Against HBV, BKV, and Other Viruses"],"prefix":"10.1002","volume":"21","author":[{"given":"Christianna H. 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