Chemical Synthesis of the Antiviral Nucleotide Analogue ddhCTP

3′-Deoxy-3′,4′-didehydro-cytidine triphosphate (ddhCTP) is a novel antiviral molecule produced by the enzyme viperin as part of the innate immune response. ddhCTP has been shown to act as an obligate chain terminator of flavivirus and SARS-CoV-2 RNA-dependent RNA polymerases; however, further biophy...

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Bibliographic Details
Published in:Journal of organic chemistry 2021-07, Vol.86 (13), p.8843-8850
Main Authors: Wood, James M, Evans, Gary B, Grove, Tyler L, Almo, Steven C, Cameron, Scott A, Furneaux, Richard H, Harris, Lawrence D
Format: Article
Language:English
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Summary:3′-Deoxy-3′,4′-didehydro-cytidine triphosphate (ddhCTP) is a novel antiviral molecule produced by the enzyme viperin as part of the innate immune response. ddhCTP has been shown to act as an obligate chain terminator of flavivirus and SARS-CoV-2 RNA-dependent RNA polymerases; however, further biophysical studies have been precluded by limited access to this promising antiviral. Herein, we report a robust and scalable synthesis of ddhCTP as well as the mono- and diphosphates ddhCMP and ddhCDP, respectively. Identification of a 2′-silyl ether protection strategy enabled selective synthesis and facile purification of the 5′-triphosphate, culminating in the preparation of ddhCTP on a gram scale.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.1c00761