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Author Notes:

For D.C.L.: phone, 404-727-6602, E-mail, dliotta@emory.edu., For K.E.G.: E-mail, kgiesle@emory.edu.

Kyle Giesler drafted the manuscript and performed the chemical synthesis.

Jose Marengo conducted stability studies and provided edits to the final manuscript.

All authors have given approval to the final version of the manuscript.

We acknowledge Manohar Saindane for transporting numerous samples from Emory to the EIDD for analysis.

The authors declare no competing financial interest.


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


Journal Title:

Journal of Medicinal Chemistry


Volume 59, Number 15


, Pages 7097-7110

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2017 American Chemical Society

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