Open AccessA Chemical Strategy for Intracellular Arming of an Endogenous Broad-Spectrum Antiviral Nucleotide
Author(s) -
Kellan T. Passow,
Haley S. Caldwell,
Kiet Ngo,
Jamie J. Arnold,
Nicole M. Antczak,
A. Narayanan,
Joyce Jose,
Shana J. Sturla,
Craig Ε. Cameron,
Alexander T. Ciota,
Daniel A. Harki
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c01481
Subject(s) - nucleotide , chemistry , endogeny , phosphoramidate , nucleoside , prodrug , intracellular , cytidine , broad spectrum , nucleic acid , virology , antiviral drug , nucleoside analogue , virus , biochemistry , biology , combinatorial chemistry , enzyme , gene
The naturally occurring nucleotide 3'-deoxy-3',4'-didehydro-cytidine-5'-triphosphate ( ddhCTP ) was recently found to exert potent and broad-spectrum antiviral activity. However, nucleoside 5'-triphosphates in general are not cell-permeable, which precludes the direct use of ddhCTP as a therapeutic. To harness the therapeutic potential of this endogenous antiviral nucleotide, we synthesized phosphoramidate prodrug HLB-0532247 ( 1 ) and found it to result in dramatically elevated levels of ddhCTP in cells. We compared 1 and 3'-deoxy-3',4'-didehydro-cytidine ( ddhC ) and found that 1 more effectively reduces titers of Zika and West Nile viruses in cell culture with minimal nonspecific toxicity to host cells. We conclude that 1 is a promising antiviral agent based on a novel strategy of facilitating elevated levels of the endogenous ddhCTP antiviral nucleotide.