Glyoxal Caging of Nucleoside\nAntivirals toward Self-Activating,\nExtended-Release Prodrugs

Nucleoside antivirals are a leading class of compounds\nprescribed\nas a first-line treatment for viral infections. However, inherent\nlimitations such as low solubility and circulation lifetime can necessitate\nmulti-intraday dosing. Here, we deploy the 1,2-dialdehyde glyoxal\nto generate antiviral nucleoside prodrugs with enhanced pharmacokinetic\nproperties and extended-release activity to combat poor patient adherence.\nThe near-quantitative reaction of glyoxal with acyclovir (ACV) drastically\nimproves ACV solubility and enables subsequent drug release with a\nhalf-life of 1.9 h under physiological conditions. Further, glyoxal\ncaging thermoreversibly disrupts ACV activity against HIV-1 reverse\ntranscription <i>in vitro</i> and HSV-1 pathology <i>in cellulo</i>. Finally, the amenability of a panel of nucleoside\nreverse transcriptase inhibitors to glyoxal caging showcases the potential\nof this highly versatile method for achieving timed-release activation\nof a clinically important class of antiviral therapeutics.