Inhibition of human hepatitis B virus DNA polymerase and duck hepatitis B virus DNA polymerase by triphosphates of thymidine analogs and pharmacokinetic properties of the corresponding nucleosides

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Abstract
Replication of hepadnaviruses involves a viral DNA polymerase containing both a DNA-dependent and an RNA dependent activity. This polymerase is a potential target for chemotherapy against hepatitis B. We have used human hepatitis B virus DNA-dependent DNA polymerase from human serum and duck hepatitis B virus DNA-dependent DNA polymerase from duck serum as well as RNA-dependent DNA polymerase activity from duck hepatitis B-infected duck liver. Triphosphates of thymidine analogs have been synthesized and tested for their inhibitory activities against these enzymes with the intention both to explore differences between these enzymes and structural requirements for inhibitors. The results showed that with the inhibitors tested, hepatitis B virus DNA-dependent DNA polymerase was the most sensitive enzyme and the triphosphate of 5-propenyl-2′-deoxyuridine was the most active inhibitor. In addition, the 5′-triposphate of 5-propenyl-arabinofuranosyluracil also inhibited the hepadnavirus DNA-dependent DNA polymerases, and was a competitive inhibitor with respect to 2′-deoxythymidine triphosphate as showed by kinetic studies with duck hepatitis B virus DNA-dependent DNA polymerase from serum. Pharmacokinetic analysis showed 5-propenyl-2′-deoxyuridine to be well absorbed orally, but rapidly cleared from plasma. The arabinofuranosyl analog was also well absorbed but cleared less rapidly. Hence, these results indicate the potential of 5-propenyl-2′-deoxyuridine and 5-propenyl-arabinofuransyluracil for chemotherapy of hepatitis B.

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