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Nucleoside antivirals are a leading class of compounds prescribed as a first-line treatment for viral infections. However, inherent limitations such as low solubility and circulation lifetime can necessitate multi-intraday dosing. Here, we deploy the 1,2-dialdehyde glyoxal to generate antiviral nucleoside prodrugs with enhanced pharmacokinetic properties and extended-release activity to combat poor patient adherence. The near-quantitative reaction of glyoxal with acyclovir (ACV) drastically improves ACV solubility and enables subsequent drug release with a half-life of 1.9 h under physiological conditions. Further, glyoxal caging thermoreversibly disrupts ACV activity against HIV-1 reverse transcription in vitro and HSV-1 pathology in cellulo. Finally, the amenability of a panel of nucleoside reverse transcriptase inhibitors to glyoxal caging showcases the potential of this highly versatile method for achieving timed-release activation of a clinically important class of antiviral therapeutics.
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Diane B. Karloff
R. Trent Stubbs
Olamilekan Joseph Ibukun
Journal of the American Chemical Society
Washington University in St. Louis
Emory University
University of Alabama at Birmingham
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Karloff et al. (Wed,) studied this question.
www.synapsesocial.com/papers/69f0be4503adddf1548f2574 — DOI: https://doi.org/10.1021/jacs.4c08371