Next-Generation Reduction Sensitive Lipid Conjugates of Tenofovir: Antiviral Activity and Mechanism of Release.

The pharmacokinetic properties of tenofovir (TFV) and other charged nucleoside analogues are dramatically improved upon conjugation to a lipid prodrug. We previously prepared reduction-sensitive lipid conjugates of TFV that demonstrate superior antiviral activity compared to other lipid conjugates including the clinically approved formulation, tenofovir disoproxil fumarate (TDF). In continuation of that work, we have synthesized next-generation conjugates with reduced cytotoxicity that retain potent antiviral activity against HIV-1 and HBV with a therapeutic index >100000 for our most potent conjugate. We also show that disulfide reduction is not responsible for prodrug cleavage unless 3-exo-tet intramolecular cyclization can occur, suggesting that enzymatic hydrolysis is predominantly responsible for activity of our prodrugs in vitro.