Viral DNA polymerase and reverse transcriptase (RT/DNA Pol)

Viral DNA polymerases and reverse transcriptases are specialized enzymes that play a central role in the replication of various viral genomes, making them critical therapeutic targets. DNA polymerases are responsible for synthesizing DNA from a DNA template, a process essential for the proliferation of DNA viruses such as herpesviruses and hepatitis B virus (HBV) [1, 2]. Reverse transcriptases, found in retroviruses like HIV and also utilized by HBV, possess the unique ability to synthesize DNA from an RNA template, a process known as reverse transcription [5, 11]. These enzymes are highly favorable targets for antiviral drugs because they are essential for the viral life cycle and often possess structural features distinct from human cellular polymerases, allowing for selective inhibition [1, 3]. Therapeutic agents targeting these enzymes include nucleoside/nucleotide analogs that act as chain terminators and non-nucleoside inhibitors that modulate enzyme activity through allosteric binding [3, 11]. While these drugs have revolutionized the treatment of chronic viral infections, the high mutation rate of viruses often leads to the development of drug resistance, necessitating combination therapies and continuous monitoring [2, 14].

Other names

Viral DNA-directed DNA polymeraseRNA-directed DNA polymeraseRetroviral reverse transcriptaseHBV polymeraseHIV-1 reverse transcriptaseHSV DNA polymeraseViral polymerase

Inhibitors of viral DNA polymerases and reverse transcriptases generally fall into three categories: nucleoside/nucleotide analogs, non-nucleoside inhibitors, and pyrophosphate analogs. Nucleoside and nucleotide analogs (e.g., NRTIs) are prodrugs that, once phosphorylated, compete with natural dNTPs for the active site; their incorporation into the nascent DNA strand causes chain termination because they lack the 3'-hydroxyl group necessary for further elongation [11]. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to a specific allosteric hydrophobic pocket, causing a conformational change that disrupts the catalytic site's function [5]. Pyrophosphate analogs, such as foscarnet, bind directly to the pyrophosphate-binding site of the enzyme, blocking the cleavage of pyrophosphate from deoxynucleotide triphosphates and thus preventing DNA chain extension [2, 8].