Reduction Sensitive Lipid Conjugates of Tenofovir: Synthesis, Stability, and Antiviral Activity

The therapeutic value of numerous
small molecules hinges on their
ability to permeate the plasma membrane. This is particularly true
for tenofovir (TFV), adefovir, and other antiviral nucleosides that
demonstrate potent antiviral activity but poor bioavailability. Using
TFV as a model substrate, we hybridized two disparate prodrug strategies
to afford novel reduction-sensitive lipid conjugates of TFV that exhibit
subnanomolar activity toward HIV-1 and are stable in human plasma
for more than 24 h with a therapeutic index approaching 30000. These
compounds significantly rival the clinically approved formulation
of TFV and revitalize the potential of disulfide-bearing prodrugs
which have seen limited in vitro and in vivo success since their debut
over 20 years ago. We further demonstrate the utility of these conjugates
as a tool to indirectly probe the enzymatic hydrolysis of phosphonomonoesters
that may further advance the development of other prodrug strategies
for nucleosides, peptides, and beyond.