2. Academic Validation
  3. A Chemical Strategy for Intracellular Arming of an Endogenous Broad-Spectrum Antiviral Nucleotide

A Chemical Strategy for Intracellular Arming of an Endogenous Broad-Spectrum Antiviral Nucleotide

  • J Med Chem. 2021 Oct 28;64(20):15429-15439. doi: 10.1021/acs.jmedchem.1c01481.
Kellan T Passow 1,  Haley S Caldwell 2 3,  Kiet A Ngo 3,  Jamie J Arnold 4,  Nicole M Antczak 5,  Anoop Narayanan 4,  Joyce Jose 4 6,  Shana J Sturla 5,  Craig E Cameron 4,  Alexander T Ciota 2 3,  Daniel A Harki 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.
  • 2 Department of Biomedical Sciences, State University of New York at Albany School of Public Health, Albany, New York 12144, United States.
  • 3 The Arbovirus Laboratory, Wadsworth Center, New York State Department of Health, Slingerlands, New York 12201, United States.
  • 4 Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
  • 5 Department of Health Sciences and Technology, ETH Zürich, Zürich 8092, Switzerland.
  • 6 Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
PMID: 34661397 DOI: 10.1021/acs.jmedchem.1c01481
Abstract

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.

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