title: Reduction Sensitive Lipid Conjugates of Tenofovir: Synthesis, Stability, and Antiviral Activity.
abstract: 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.
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive NE, Atlanta, Georgia 30322, United States.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Giesler
authors.affiliation: Emory Institute for Drug Development , 954 Gatewood Road, Atlanta, Georgia 30329, United States.
authors.forename: Jose
authors.initials: J
authors.lastname: Marengo
authors.affiliation: Department of Chemistry, Emory University , 1521 Dickey Drive NE, Atlanta, Georgia 30322, United States.|Emory Institute for Drug Development , 954 Gatewood Road, Atlanta, Georgia 30329, United States.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects*; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008055:Lipids / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D000068698:Tenofovir / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D008055:Lipids; D000068698:Tenofovir