Carbocyclic dinucleoside polyphosphonates: interaction with HIV reverse transcriptase and antiviral activity

Area of Science:

• Biochemistry
• Virology
• Drug Delivery

Background:

• HIV reverse transcriptase is a key target for antiviral therapy.
• Nucleoside analogues are a significant class of antiviral drugs.
• Developing novel inhibitors with improved efficacy is crucial.

Purpose of the Study:

• To investigate carbocyclic bis(nucleoside) phosphonates as potential HIV reverse transcriptase inhibitors.
• To evaluate the antiviral activity of these analogues in cell-based models.
• To assess the impact of liposome delivery on their efficacy.

Main Methods:

• Synthesis and characterization of carbocyclic alpha, gamma-bis(nucleoside)-5,5'-triphosphonates and alpha, delta-bis(nucleoside)-5,5'-tetraphosphonates.
• Assay of enzyme inhibition using HIV reverse transcriptase in cell-free systems.
• Antiviral activity testing in Rat1 fibroblast and HIV-infected MT-4 cell cultures.
• Evaluation of liposome-encapsulated compounds for enhanced delivery.

Main Results:

• The synthesized analogues (Ap4A and Gp4G) acted as terminating substrates for HIV reverse transcriptase.
• Effective inhibition of DNA synthesis was observed in cell-free enzyme assays.
• Low antiviral activity was noted in both MLV-infected Rat1 cells and HIV-infected MT-4 cells.
• Liposome-mediated delivery significantly increased the antiviral efficacy of the compounds.

Conclusions:

• Carbocyclic bis(nucleoside) phosphonates are novel terminating substrates for HIV reverse transcriptase.
• Their intrinsic antiviral activity is limited, but can be enhanced by liposome formulation.
• Liposome delivery systems show promise for improving the therapeutic potential of these compounds against HIV.