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Scalable Synthesis and Biological Evaluation of 3′-Deoxy-3′,4′-didehydronucleoside Triphosphates

Year: 2026
Type: article
Abstract: 3'-Deoxy-3',4'-didehydronucleoside triphosphates (ddhNTPs) are antiviral metabolites produced by viperin and viperin-like enzymes, all of which are members of the radical SAM superfamily of enzymes. To date, synthetic access to ddhUTP, ddhGTP, and ddhATP has remained limited. We report a scalable synthesis of the complete ddhN nucleoside family using Bobbitt's salt-mediated oxidation of nucleoside orthoformates, including a chromatography-free route to ddhC on a gram scale. This methodology enabled the first synthesis and evaluation of ddhUTP, ddhGTP, and ddhATP as inhibitors of RNA-dependent RNA polymerases, with ddhATP confirmed to act as an obligate chain terminator through primer extension assays.
DOI: 10.1021/acs.joc.6c00483
Authors: James M. Wood, Dan G. Torres, Roselis A. Landaeta Aponte, Sandesh Deshpande, Alice M. McSweeney, Rinu Shrestha, Andrew Reddy, Gary B. Evans, Steven C. Almo, Tyler L. Grove, Richard L. Kingston, Vernon K. Ward, Lawrence D. Harris
Institutions: University of Auckland, Victoria University of Wellington, Maurice Wilkins Centre, Ferrier Research Institute, University of Otago, Albert Einstein College of Medicine
Language: English
Open Access status: green
OpenAlex ID: W7160188385
FWCI: 2.044
Cites: 29
Cited by: 1
Related to: 10