Polymerase protein

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 [1].

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 [2].

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 [3].


Bibliographic references

  1. Hepatitis B viruses: reverse transcription a different way.
    Nassal M.
    Virus Res, 2008, 134(1-2):235-249.

  2. Hepatitis B virus resistance to nucleos(t)ide analogues.
    Zoulim F., Locarnini S.
    Gastroenterology, 2009, 137(5):1593-1608.

  3. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection.
    European Association For The Study Of The Liver
    J Hepatol, 2012, 57(1):167-185.