Improved antiviral activity of the aryloxymethoxyalaninyl phosphoramidate (APA) prodrug of abacavir (ABC) is due to the formation of markedly increased carbovir 5′‐triphosphate metabolite levels
Open Access
- 28 July 2004
- journal article
- Published by Wiley in FEBS Letters
- Vol. 573 (1-3) , 38-44
- https://doi.org/10.1016/j.febslet.2004.07.049
Abstract
The anti‐human immunodeficiency virus (HIV) activity of abacavir (ABC; 1‐(1S,4R)‐4‐[2‐amino‐6‐(cyclopropylamino)‐9H‐purin‐9‐yl]‐2‐cyclopentene‐1‐methanol) could be markedly enhanced by administering the aryloxymethoxyalaninyl phosphoramidate prodrug derivative of ABC (pro‐ABC‐MP) to virus‐infected cell cultures. Metabolic studies with radiolabeled ABC and pro‐ABC‐MP in human T‐lymphocyte and primary macrophage cell cultures revealed a significantly increased delivery of the activated (phosphorylated) metabolite of ABC (ABC‐MP) by pro‐ABC‐MP, and the concomittant appearance of markedly higher intracellular levels of carbovir 5′‐triphosphate (CBV‐TP), which represents the eventual antivirally active metabolite of ABC. The intracellular amounts of ABC‐MP and appearance of CBV‐TP closely correlated with the extracellular pro‐ABC‐MP concentrations that were administered to the cell cultures within a concentration range between 0.5 and 100 μM. The highest amounts of CBV‐TP were observed within 6–24 h after drug administration. The improved delivery of ABC‐MP and metabolic conversion to CBV‐TP explain the markedly enhanced antiviral activity of the prodrug of ABC, and warrant further exploration of this prodrug technology on ABC and related compounds to further enhance and optimize their antiviral efficacy.Keywords
This publication has 22 references indexed in Scilit:
- Rational design for cytosolic delivery of nucleoside monphosphates : “SATE” and “DTE” as enzyme-labile transient phosphate protecting groupsPublished by Elsevier ,2001
- Activities of Masked 2′,3′-Dideoxynucleoside Monophosphate Derivatives against Human Immunodeficiency Virus in Resting MacrophagesAntimicrobial Agents and Chemotherapy, 2000
- cycloSal-Pronucleotides of 2‘,3‘-Dideoxyadenosine and 2‘,3‘-Dideoxy-2‘,3‘-didehydroadenosine: Synthesis and Antiviral Evaluation of a Highly Efficient Nucleotide Delivery SystemJournal of Medicinal Chemistry, 1999
- cycloSal-2‘,3‘-dideoxy-2‘,3‘-didehydrothymidine Monophosphate (cycloSal-d4TMP): Synthesis and Antiviral Evaluation of a New d4TMP Delivery SystemJournal of Medicinal Chemistry, 1998
- Phosphoramidate derivatives of 2′,3′-didehydro-2′,3′-dideoxyadenosine [d4A] have markedly improved anti-HIV potency and selectivityBioorganic & Medicinal Chemistry Letters, 1996
- Anti-HIV and Anti-HBV Activity and Resistance Profile of 2′,3′-Dideoxy-3′-Thiacytidine (3TC) and Its Arylphosphoramidate Derivative CF 1109Biochemical and Biophysical Research Communications, 1996
- Aryl Phosphoramidate Derivatives of d4T Have Improved Anti-HIV Efficacy in Tissue Culture and May Act by the Generation of a Novel Intracellular MetaboliteJournal of Medicinal Chemistry, 1996
- Unique purine crossover activation pathway for the potent anti-HIV agent 1592U89Antiviral Research, 1995
- Masked nucleotides: A strategy to introduce therapeutic nucleoside 5′-phosphates into cellsAntiviral Research, 1991
- Potent and selective activity of a new carbocyclic nucleoside analog (Carbovir: NSC 614846) against human immunodeficiency virus In vitroBiochemical and Biophysical Research Communications, 1988