The Polymerase (Pol) contains between 832 or 845 amino acids (aa) depending on the genotypes. This enzyme exhibits both a DNA-dependent DNA polymerase and a RNA-dependent DNA polymerase (reverse transcriptase) activities. It replicates the HBV genome from an encapsidated pregenomic RNA template. Initiation of DNA synthesis occurs by a unique protein-priming mechanism, involving a conserved tyrosine residue of the terminal protein (TP) domain and the pgRNA ε stem-loop structure. Once the DNA minus-strand is synthetized, RNase H degrades the RNA template and HBV Pol starts the synthesis of plus-strand DNA, leading to the formation of relaxed-circular (RC) form of the HBV genome .
The viral polymerase is composed of 4 domains, bearing 3 enzymatic activities (Figure 1):
Figure1. The polymerase numbering is defined based on the HBVdb X02763 protein numbering.
Polymerase inhibitors: Nucleos(t)ide analogs
Nucleos(t)ide analogs (NA) inhibit the reverse transcriptase activity of the HBV polymerase. Patients with chronic hepatitis B (CHB) can be successfully treated using nucleos(t)ide analogs (NA), but drug-resistant HBV mutants may arise, leading to treatment failure and progression to liver disease .
Interferon (conventional or pegylated) and 5 other drugs that belong to the class of nucleos(t)ide analogues (NA) (lamivudine [LMV], adefovir dipivoxil [ADV], entecavir [ETV], telbivudine [LdT], and tenofovir [TDF]) have been approved for treatment of CHB in many parts of the world .
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