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Adenosine Dioxolane Nucleoside Phosphoramidates as Antiviral Agents for Human Immunodeficiency and Hepatitis B

Lavanya Bondada1, Mervi Detorio, Leda Bassit

  • 1Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, Georgia 30033, USA.

ACS Medicinal Chemistry Letters
|September 10, 2013
PubMed

Insights

Novel phosphoramidate prodrugs targeting HIV and HBV show significantly enhanced antiviral potency. These C-6 modified nucleoside analogs demonstrate improved efficacy without significant cytotoxicity, offering a promising advancement in antiviral therapies.

Area of Science:

  • Medicinal Chemistry
  • Virology
  • Pharmacology

Background:

  • Nucleoside reverse transcriptase inhibitors (NRTIs) are crucial for HIV treatment, requiring intracellular phosphorylation to active triphosphate forms.
  • Developing potent and safe antiviral agents against HIV and Hepatitis B Virus (HBV) remains a global health priority.

Purpose of the Study:

  • To synthesize novel C-6 modified (-)-β-D-(2R,4R)-1,3-dioxolane adenosine nucleosides and nucleotides.
  • To evaluate the antiviral activity and cytotoxicity of newly developed phosphoramidate prodrugs against HIV-1 and HBV.
  • To investigate the potential of a novel phosphoramidate prodrug technology to enhance NRTI efficacy.

Main Methods:

  • Synthesis of C-6 modified (-)-β-D-(2R,4R)-1,3-dioxolane adenosine nucleosides and phosphoramidate prodrugs.
  • Antiviral assays to determine potency against HIV-1 and HBV.
  • Cytotoxicity assessments in various cell systems to determine CC50 values.

Main Results:

  • Synthesized phosphoramidate prodrugs exhibited significantly enhanced potency against HIV-1 (up to 3,600-fold) and HBV (up to 300-fold) compared to parent nucleosides.
  • Most compounds showed no cytotoxicity up to 100 μM, with specific compounds (17 and 18) displaying CC50 values of 7.3 and 12 μM in Huh-7 cells.
  • Increased intracellular formation of adenosine dioxolane triphosphate was observed, contributing to the dual antiviral activity.

Conclusions:

  • Novel phosphoramidate prodrugs demonstrate potent dual antiviral activity against HIV and HBV.
  • The prodrug approach enhances intracellular delivery and activation of nucleoside analogs.
  • These compounds represent promising candidates for further development in antiviral therapy with reduced toxicity profiles.
Keywords:
Dioxolane adenosine nucleosideHBVHIVProTidenucleoside reverse transcriptase inhibitorphosphoramidate prodrug

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