DNA-directed DNA polymerase catalytic subunit (Herpesvirus) (DNA pol)

The DNA-directed DNA polymerase catalytic subunit is a critical enzyme for the replication of herpesvirus genomes, including Human Cytomegalovirus (HCMV), Herpes Simplex Virus (HSV), and Varicella-Zoster Virus (VZV) [1, 4]. In HCMV, this enzyme is encoded by the UL54 gene and functions as a Family B DNA polymerase that works in complex with the processivity factor UL44 to synthesize long-chain viral DNA during the lytic phase of infection [11, 17]. The enzyme possesses multiple catalytic activities, including 5'-3' polymerase activity, 3'-5' exonuclease proofreading, and ribonuclease H activity, which are essential for high-fidelity genome duplication [1, 14]. This polymerase is the primary therapeutic target for most approved anti-herpetic drugs, which fall into two main categories: nucleoside/nucleotide analogs and pyrophosphate analogs [8, 21]. Nucleoside analogs like ganciclovir and acyclovir are phosphorylated to active triphosphate forms that compete with natural nucleotides for incorporation into the growing DNA strand, leading to chain termination [6, 23]. Pyrophosphate analogs, such as foscarnet, bind directly to the enzyme's pyrophosphate exit site to block nucleotide incorporation without requiring prior activation [8, 20]. Clinical challenges include significant drug-induced toxicities, such as nephrotoxicity and bone marrow suppression, and the emergence of drug-resistant viral strains harboring mutations in the polymerase gene, particularly in immunocompromised patients [16, 21].

Other names

UL54 (Cytomegalovirus)UL30 (Herpes simplex virus)ORF28 (Varicella-zoster virus)BALF5 (Epstein-Barr virus)U38 (Human herpesvirus 6/7)ORF9 (Human herpesvirus 8)Herpesvirus DNA polymerasePol

Nucleoside and nucleotide analogs act as competitive inhibitors of deoxyribonucleotide triphosphate (dNTP) binding and often function as DNA chain terminators upon incorporation into the viral DNA strand [8, 23]. Pyrophosphate analogs, such as foscarnet, non-competitively inhibit the enzyme by binding to the pyrophosphate binding site, thereby preventing the cleavage of pyrophosphate from deoxynucleoside triphosphates and halting DNA chain elongation [8, 20].