Expanding the toolbox of metabolically stable lipid prodrug strategies
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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1083284/full |
| _version_ | 1797959917057867776 |
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| author | Kiran S. Toti Nicole Pribut Michael D’Erasmo Madhuri Dasari Savita K. Sharma Perry W. Bartsch Samantha L. Burton Samantha L. Burton Samantha L. Burton Hannah B. Gold Anatoliy Bushnev Cynthia A. Derdeyn Cynthia A. Derdeyn Cynthia A. Derdeyn Cynthia A. Derdeyn Adriaan E. Basson Dennis C. Liotta Eric J. Miller |
| author_facet | Kiran S. Toti Nicole Pribut Michael D’Erasmo Madhuri Dasari Savita K. Sharma Perry W. Bartsch Samantha L. Burton Samantha L. Burton Samantha L. Burton Hannah B. Gold Anatoliy Bushnev Cynthia A. Derdeyn Cynthia A. Derdeyn Cynthia A. Derdeyn Cynthia A. Derdeyn Adriaan E. Basson Dennis C. Liotta Eric J. Miller |
| author_sort | Kiran S. Toti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T00:38:17Z |
| format | Article |
| id | doaj.art-95897a2077a94f00b1666c0194367d18 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T00:38:17Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-95897a2077a94f00b1666c0194367d182023-01-06T13:38:48ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-01-011310.3389/fphar.2022.10832841083284Expanding the toolbox of metabolically stable lipid prodrug strategiesKiran S. Toti0Nicole Pribut1Michael D’Erasmo2Madhuri Dasari3Savita K. Sharma4Perry W. Bartsch5Samantha L. Burton6Samantha L. Burton7Samantha L. Burton8Hannah B. Gold9Anatoliy Bushnev10Cynthia A. Derdeyn11Cynthia A. Derdeyn12Cynthia A. Derdeyn13Cynthia A. Derdeyn14Adriaan E. Basson15Dennis C. Liotta16Eric J. Miller17Department of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesDepartment of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesDepartment of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesDepartment of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesDepartment of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesDepartment of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesDepartment of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesEmory National Primate Research Center, Emory University, Atlanta, GA, United StatesEmory Vaccine Center, Emory University, Atlanta, GA, United StatesDepartment of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesDepartment of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesEmory National Primate Research Center, Emory University, Atlanta, GA, United StatesEmory Vaccine Center, Emory University, Atlanta, GA, United StatesDepartment of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA, United StatesDepartment of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United StatesHIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg, Gauteng, South AfricaDepartment of Chemistry, College of Arts and Sciences, Emory University, Atlanta, GA, United StatesDepartment of Pharmacology and Chemical Biology, School of Medicine, Emory University, Atlanta, GA, United StatesNucleoside- 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.https://www.frontiersin.org/articles/10.3389/fphar.2022.1083284/fullprodrugsHIVtenofovirmetabolismlipidsnucleoside |
| spellingShingle | Kiran S. Toti Nicole Pribut Michael D’Erasmo Madhuri Dasari Savita K. Sharma Perry W. Bartsch Samantha L. Burton Samantha L. Burton Samantha L. Burton Hannah B. Gold Anatoliy Bushnev Cynthia A. Derdeyn Cynthia A. Derdeyn Cynthia A. Derdeyn Cynthia A. Derdeyn Adriaan E. Basson Dennis C. Liotta Eric J. Miller Expanding the toolbox of metabolically stable lipid prodrug strategies Frontiers in Pharmacology prodrugs HIV tenofovir metabolism lipids nucleoside |
| title | Expanding the toolbox of metabolically stable lipid prodrug strategies |
| title_full | Expanding the toolbox of metabolically stable lipid prodrug strategies |
| title_fullStr | Expanding the toolbox of metabolically stable lipid prodrug strategies |
| title_full_unstemmed | Expanding the toolbox of metabolically stable lipid prodrug strategies |
| title_short | Expanding the toolbox of metabolically stable lipid prodrug strategies |
| title_sort | expanding the toolbox of metabolically stable lipid prodrug strategies |
| topic | prodrugs HIV tenofovir metabolism lipids nucleoside |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1083284/full |
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