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.
We sought to design disulfide-linked lipid conjugates that readily permeate the plasma membrane and rapidly releases the nucleoside within the target cell without the need for enzymatic activation. In contrast to other prodrug strategies, our design relies on the reduction-sensitive nature of the S–S bond that selectively bows to the universal glutathione redox potential that exists at the plasma membrane between the extra- and intracellular milieu.Glutathione, often referred to as GSH, is a tripeptide typically stockpiled in millimolar concentrations (2–10 mM) within the cytosol that participates in a multitude of biological functions to promote the reduction of disulfides, detoxification of xenobiotics, mediate immunoregulation, and curb oxidative stress32 among others. GSH is seldom found in the extracellular space and thus creates a gradient that fosters intracellular reduction of disulfides and simultaneously promotes an oxidative environment to support S–S formation in the surrounding media. (J Med Chem. 2016 Aug 11; 59(15): 7097–7110.)