DNA and RNA polymerases

DNA and RNA polymerases are a diverse class of enzymes essential for the synthesis of nucleic acid polymers, playing fundamental roles in genome replication, maintenance, and gene expression across all domains of life (Source 1.2.1, 1.4.3). These enzymes are categorized by their template and product, including DNA-directed DNA polymerases for genome duplication, RNA-directed DNA polymerases (reverse transcriptases) for retroviral replication, and RNA-directed RNA polymerases for the replication of many RNA viruses (Source 1.1.2, 1.2.1). In clinical medicine, they are among the most significant therapeutic targets for treating viral infections (e.g., HIV, Hepatitis B and C, COVID-19), bacterial diseases (e.g., tuberculosis), and various cancers (Source 1.1.1, 1.4.1). Antiviral and antibacterial strategies often leverage structural differences between pathogen and host enzymes to achieve selectivity, frequently utilizing nucleoside analogs that act as chain terminators (Source 1.1.2, 1.2.1). In oncology, inhibitors of human polymerases are employed to disrupt the rapid DNA synthesis characteristic of malignant cells (Source 1.2.1, 1.2.5). However, the effectiveness of these therapies is often challenged by the development of drug-resistant mutations and potential off-target toxicities, such as the inhibition of human mitochondrial DNA polymerase gamma, which can lead to severe systemic adverse effects like lactic acidosis and organ damage (Source 1.5.1, 1.5.3).

Other names

NucleotidyltransferasesDNA-directed DNA polymeraseRNA-directed DNA polymeraseDNA-directed RNA polymeraseRNA-directed RNA polymeraseReverse transcriptaseRNA-dependent RNA polymerase (RdRp)DNA-dependent DNA polymerase

Drugs targeting these enzymes primarily act as nucleoside or nucleotide analogs that compete with natural substrates for the active site, leading to premature chain termination upon incorporation into the nascent nucleic acid strand (Source 1.1.2, 1.2.1). Non-nucleoside inhibitors (NNIs) bind to allosteric sites, inducing conformational changes that inhibit enzymatic activity (Source 1.1.2). Other agents, such as actinomycin D, intercalate into the DNA template to physically block the progression of the polymerase (Source 1.1.4, 1.2.5). Additionally, some mutagenic agents increase the error rate of the polymerase to induce lethal mutagenesis in viral populations (Source 1.1.2).