Chemical Synthesis of the Antiviral Nucleotide Analogue ddhCTP

J Org Chem. 2021 Jul 2;86(13):8843-8850. doi: 10.1021/acs.joc.1c00761. Epub 2021 Jun 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents*
  • COVID-19*
  • Cytidine Triphosphate
  • Humans
  • Proteins
  • RNA, Viral
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • Proteins
  • RNA, Viral
  • Cytidine Triphosphate