Hepatitis B virus polymerase (HBV Pol)

The Hepatitis B virus (HBV) polymerase is a multi-functional enzyme essential for the replication of the HBV genome, which occurs via an RNA intermediate (UniProt: P03156). It consists of four distinct domains: the terminal protein, a spacer, the reverse transcriptase (RT) domain, and the RNase H domain (PubMed: PMC4931144). The RT domain contains the catalytic active site responsible for both RNA-dependent DNA polymerase activity and DNA-dependent DNA polymerase activity, which are required to synthesize the viral DNA genome (NCBI: NBK532237). This active site is the primary target for current standard-of-care antiviral therapies, specifically nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) (StatPearls: NBK541064). These drugs act as competitive inhibitors that, once incorporated into the nascent DNA chain, cause premature chain termination (PubMed: 26230544). While these therapies effectively suppress viral replication, they do not eliminate the viral cccDNA reservoir, and long-term use can lead to the selection of drug-resistant mutations within the RT active site (PubMed: 18028434).

Other names

Hepatitis B virus reverse transcriptaseHBV RTP proteinRNA-directed DNA polymeraseDNA-directed DNA polymeraseHBV reverse transcriptase active site

Nucleoside and nucleotide analogs (NRTIs) compete with natural deoxynucleotides for binding to the active site of the HBV reverse transcriptase. Once incorporated into the growing DNA strand, these analogs cause premature chain termination because they lack the 3'-hydroxyl group necessary for the formation of the next phosphodiester bond (PubMed: 26230544).