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Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis
J L Martin1, C E Brown, N Matthews-Davis
1Division of Virology, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
Abstract:
Inhibition constants were determined for 16 nucleoside analog triphosphates against human DNA polymerases alpha, beta, gamma, and epsilon, and 7 nucleoside analogs were examined as inhibitors of mitochondrial DNA synthesis in human Molt-4 cells in culture. The results demonstrate no clear quantitative or qualitative correlation between inhibition of DNA polymerases, particularly mitochondrial DNA polymerase gamma, and the inhibition of mitochondrial DNA synthesis in Molt-4 cell culture. Furthermore, the data indicate that inhibition of isolated DNA polymerases may not be predictive of in vitro or in vivo toxicity. Finally, it is not clear whether inhibition of mitochondrial DNA synthesis will be an accurate predictor of the potential in vivo toxicity of antiviral nucleoside analogs.
Insights
Inhibiting human DNA polymerases does not reliably predict effects on mitochondrial DNA synthesis or cellular toxicity. Further research is needed to understand antiviral nucleoside analog toxicity.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Nucleoside analogs are crucial antiviral agents.
- Their efficacy and toxicity are linked to DNA synthesis inhibition.
- Predicting cellular toxicity from DNA polymerase inhibition remains challenging.
Purpose of the Study:
- To investigate the relationship between DNA polymerase inhibition and mitochondrial DNA synthesis.
- To assess the predictive value of DNA polymerase inhibition for cellular toxicity.
- To evaluate mitochondrial DNA synthesis inhibition as a predictor of in vivo toxicity for antiviral nucleoside analogs.
Main Methods:
- Determined inhibition constants for 16 nucleoside analog triphosphates against human DNA polymerases (alpha, beta, gamma, epsilon).
- Examined 7 nucleoside analogs as inhibitors of mitochondrial DNA synthesis in human Molt-4 cells.
- Correlated DNA polymerase inhibition with observed effects on mitochondrial DNA synthesis and cellular toxicity.
Main Results:
- No clear correlation was found between DNA polymerase inhibition and mitochondrial DNA synthesis inhibition.
- Inhibition of isolated DNA polymerases did not reliably predict in vitro or in vivo toxicity.
- The predictive value of mitochondrial DNA synthesis inhibition for in vivo toxicity is uncertain.
Conclusions:
- Inhibition of specific human DNA polymerases does not accurately predict effects on mitochondrial DNA synthesis.
- Assessing DNA polymerase inhibition alone is insufficient for predicting the toxicity of nucleoside analogs.
- Further studies are required to establish reliable biomarkers for predicting the in vivo toxicity of antiviral nucleoside analogs.