Expanding the toolbox of metabolically stable lipid prodrug strategies

• Type of Material: Article
• Authors: Kiran S Toti, Emory University; Nicole Pribut, Emory University; Michael D'Erasmo, Emory University; Madhuri Dasari, Emory University; Savita K Sharma, Emory University; Perry W Bartsch, Emory University; Samantha L Burton, Emory University; Hannah B Gold, Emory University; Anatoliy Bushnev, Emory University; Cynthia Derdeyn, Emory University; Adriaan E Basson, University of Witwatersrand; Dennis Liotta, Emory University; Eric Miller, Emory University
• Language: English
• Date: 2023-01-06
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Toti, Pribut, D’Erasmo, Dasari, Sharma, Bartsch, Burton, Gold, Bushnev, Derdeyn, Basson, Liotta and Miller.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fphar.2022.1083284
• Title of Journal or Parent Work: FRONTIERS IN PHARMACOLOGY
• Volume: 13
• Start Page: 1083284
• End Page: 1083284
• Keywords: ANTIVIRAL ACTIVITY; tenofovir; antiviral; HIV; MECHANISM; HEPATITIS-B; DRUG; ACYCLIC NUCLEOSIDE PHOSPHONATES; metabolism; prodrugs; EMTRICITABINE; Life Sciences & Biomedicine; Science & Technology; nucleotide; nucleoside; SUSCEPTIBILITY; CAPECITABINE; TENOFOVIR DISOPROXIL FUMARATE; PHARMACOLOGY; Pharmacology & Pharmacy; lipids
• Research Categories: Health Sciences, Pathology; Health Sciences, Pharmacology; Chemistry, General

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.