DNA polymerase (DNAP) (DNAP)

DNA polymerase is a fundamental enzyme class responsible for synthesizing new DNA strands by catalyzing the addition of nucleotides to a primer template during DNA replication and repair (UniProt, 2024). As the central component of the DNA elongation machinery, it works in coordination with accessory proteins like the sliding clamp (PCNA in eukaryotes) and helicases to ensure the high-fidelity duplication of the genome (NCBI, 2022). Because rapid and uncontrolled cell division is a hallmark of both cancer and viral replication, DNA polymerases serve as critical therapeutic targets for a wide range of clinical indications (Nature Reviews Drug Discovery, 2018). Drugs targeting these enzymes, such as cytarabine for leukemia or acyclovir for herpesvirus, often function as nucleoside analogs that induce premature chain termination or competitively inhibit substrate binding (PubMed, 2021). A primary challenge in the clinical use of these agents is achieving selectivity for viral or malignant polymerases over host enzymes to avoid systemic toxicities like myelosuppression or mitochondrial damage (StatPearls, 2023).

Other names

DNA-directed DNA polymeraseDNA replication machineryDNA elongation complexDNA nucleotidyltransferaseDNA elongation machinery

Drugs targeting DNA polymerase primarily act as nucleoside or nucleotide analogs. These agents are intracellularly phosphorylated into their active triphosphate forms, which then compete with natural deoxynucleotide triphosphates (dNTPs) for binding to the enzyme's active site. Upon incorporation into the nascent DNA strand, these analogs typically cause premature chain termination due to the absence of a 3'-hydroxyl group or induce structural distortions that stall the DNA elongation machinery (StatPearls, 2023; PubMed, 2021).