Hepatitis B virus DNA-directed DNA polymerase (HBV Pol)

The Hepatitis B virus (HBV) DNA-directed DNA polymerase, also known as the P protein, is a multifunctional enzyme critical for the replication of the HBV genome (UniProt P03156). It consists of four distinct domains: the terminal protein (TP) involved in protein priming, a spacer region, the reverse transcriptase (RT) domain, and the RNase H domain (PubMed: 25231598). The enzyme is responsible for converting the pregenomic RNA (pgRNA) into the partially double-stranded relaxed circular DNA (rcDNA) found in mature virions through a process involving both RNA-directed and DNA-directed DNA synthesis (NCBI: NBK532237). Because of its central role in the viral life cycle, it is the primary therapeutic target for chronic hepatitis B, specifically for nucleos(t)ide analogs like entecavir and tenofovir. These drugs act as chain terminators to inhibit viral replication; however, they typically do not achieve a complete cure as they fail to eliminate the stable covalently closed circular DNA (cccDNA) reservoir in the host cell nucleus (PubMed: 28438237).

Other names

P proteinHBV polymeraseReverse transcriptaseRNA-directed DNA polymeraseDNA-directed DNA polymerase (Hepatitis B virus)

Nucleos(t)ide analogs (NAs) compete with natural deoxynucleotides for incorporation into the nascent viral DNA strand by the HBV polymerase; once incorporated, they cause premature chain termination because they lack the 3-hydroxyl group necessary for further phosphodiester bond formation (StatPearls: NBK470430).