Expanding the toolbox of metabolically stable lipid prodrug strategies

Kiran S Toti; Nicole Pribut; Michael D'Erasmo; Madhuri Dasari; Savita K Sharma; Perry W Bartsch; Samantha L Burton; Hannah B Gold; Anatoliy Bushnev; Cynthia A Derdeyn; Adriaan E Basson; Dennis C Liotta; Eric J Miller

doi:10.3389/fphar.2022.1083284

Expanding the toolbox of metabolically stable lipid prodrug strategies

Front Pharmacol. 2023 Jan 6:13:1083284. doi: 10.3389/fphar.2022.1083284. eCollection 2022.

Authors

Kiran S Toti¹, Nicole Pribut¹, Michael D'Erasmo¹, Madhuri Dasari¹, Savita K Sharma¹, Perry W Bartsch¹, Samantha L Burton^{1

2

3}, Hannah B Gold¹, Anatoliy Bushnev¹, Cynthia A Derdeyn^{2

3

4

5}, Adriaan E Basson⁶, Dennis C Liotta¹, Eric J Miller⁷

Affiliations

¹ Department of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United States.
² Emory National Primate Research Center, Emory University, Atlanta, GA, United States.
³ Emory Vaccine Center, Emory University, Atlanta, GA, United States.
⁴ Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA, United States.
⁵ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States.
⁶ HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, Gauteng, South Africa.
⁷ Department of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, United States.

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.

Keywords: HIV; antiviral; lipids; metabolism; nucleoside; nucleotide; prodrugs; tenofovir.

Abstract

Grants and funding