DNA polymerase (DNAP) (DNAP)

DNA polymerases are essential enzymes that catalyze the synthesis of DNA molecules from deoxyribonucleotides, playing a central role in DNA replication and repair (UniProt). They function by adding nucleotides to the 3'-OH end of a growing DNA strand, guided by a template strand (NIH). In therapeutic contexts, the DNA polymerase active site is a major target for antiviral and anticancer drugs (PubChem). Nucleoside analogs, such as acyclovir and cytarabine, act as suicide substrates that are incorporated into the DNA, leading to chain termination or inhibition of further synthesis (StatPearls). Because cancer cells and viruses rely heavily on rapid DNA replication, these inhibitors can selectively disrupt their proliferation (PubMed). However, challenges include off-target effects on host cell polymerases, such as mitochondrial DNA polymerase gamma, which can lead to significant toxicities like myelosuppression and organ damage (NIH).

Other names

DNA-directed DNA polymeraseReplisomeDNA nucleotidyltransferaseDNA synthesis machineryDNA replication complex

Drugs targeting DNA polymerases primarily act as nucleoside or nucleotide analogs that compete with natural substrates for the active site. Upon incorporation into the nascent DNA strand, they typically cause premature chain termination or inhibit the enzyme's catalytic activity. Other mechanisms include allosteric inhibition and mimicry of pyrophosphate to block the release of the byproduct during nucleotide addition.