Chemical Synthesis of the Antiviral Nucleotide Analogue ddhCTP.

Abstract

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.