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.
Original language | English (US) |
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Pages (from-to) | 15429-15439 |
Number of pages | 11 |
Journal | Journal of medicinal chemistry |
Volume | 64 |
Issue number | 20 |
DOIs | |
State | Published - Oct 28 2021 |
Bibliographical note
Funding Information:We gratefully acknowledge NIH R01-GM110129 (D.A.H.), R21-AI146856 (A.T.C.), and R01-AI045818 (C.E.C. and J.J.A.), as well as a Grant-in-Aid from the Office of the Vice President for Research, University of Minnesota, for financial support. Mass spectrometry was performed at the Analytical Biochemistry core facility of the University of Minnesota Masonic Cancer Center, which is supported by NIH P30-CA77598.
Publisher Copyright:
© 2021 American Chemical Society.