Expanding the toolbox of metabolically stable lipid prodrug strategies

Abstract

Nucleoside- and nucleotide-based therapeutics are indispensable treatment options for patients suffering from malignant and viral diseases. These agents are most commonly administered to patients as prodrugs to maximize bioavailability and efficacy. While the literature provides a practical prodrug playbook to facilitate the delivery of nucleoside and nucleotide therapeutics, small context-dependent amendments to these popular prodrug strategies can drive dramatic improvements in pharmacokinetic (PK) profiles. Herein we offer a brief overview of current prodrug strategies, as well as a case study involving the fine-tuning of lipid prodrugs of acyclic nucleoside phosphonate tenofovir (TFV), an approved nucleotide HIV reverse transcriptase inhibitor (NtRTI) and the cornerstone of combination antiretroviral therapy (cART). Installation of novel lipid terminal motifs significantly reduced fatty acid hepatic ω-oxidation while maintaining potent antiviral activity. This work contributes important insights to the expanding repertoire of lipid prodrug strategies in general, but particularly for the delivery and distribution of acyclic nucleoside phosphonates.

Recent Advances in Molecular Mechanisms of Nucleoside Antivirals

“…An increase in prodrug stability to hepatocyte metabolism should reduce hepatotoxicity. Indeed, three parameters of a lipid substitute that contribute to reducing hepatotoxicity were identified: (1) a chain length of 19–21 atoms, (2) the presence of an oxygen atom in the chain, and (3) the presence of a poorly metabolizable terminal group that impedes the oxidation of the substitute in the liver [ 128 ]. Thus, impressive improvements in the stability of the tenofovir lipid prodrug tenofovir exalidex to hepatic enzymes were achieved ( Figure 22 ).…”