Work

Glyoxal Caging of Nucleoside Antivirals toward Self-Activating, Extended-Release Prodrugs

Year: 2024

Type: article

Abstract: 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.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.4c08371

Authors: Diane B. Karloff, R. Trent Stubbs, Olamilekan J. Ibukun, Steve D. Knutson, Scott H. James, Jennifer M. Heemstra

Institutions: Emory University, Washington University in St. Louis, University of Alabama at Birmingham

Language: English

Topic: HIV/AIDS drug development and treatment

Subfield: Infectious Diseases

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green