Cytomegalovirus DNA polymerase catalytic subunit (UL54)

The Cytomegalovirus DNA polymerase catalytic subunit, encoded by the UL54 gene, is an essential enzyme for the replication of the human cytomegalovirus (HCMV) genome. It operates as a DNA-directed DNA polymerase, facilitating the synthesis of viral DNA during the lytic phase of infection (UniProt P08546). The enzyme also exhibits 3'-5' exonuclease activity, which provides a proofreading function to maintain replication fidelity (PubMed: 12857911). This polymerase is a well-established therapeutic target for several antiviral agents, including ganciclovir, foscarnet, and cidofovir (NIH: PMC7127481). These drugs work by inhibiting the enzyme's activity, either through competitive inhibition as nucleoside/nucleotide analogs or by blocking the pyrophosphate binding site (PubMed: 11486059). Despite their efficacy, the clinical utility of these drugs is often limited by significant toxicities, such as myelosuppression and nephrotoxicity. Furthermore, the emergence of resistance-conferring mutations in the UL54 gene remains a major hurdle in the treatment of HCMV in immunocompromised patients and neonates (PubMed: 31434747).

Other names

UL54CMV DNA polymeraseHuman cytomegalovirus DNA polymeraseDPOL_HCMVADNA-directed DNA polymerase

Inhibition of viral DNA synthesis through competitive inhibition of deoxyribonucleoside triphosphate (dNTP) incorporation, leading to DNA chain termination (nucleoside/nucleotide analogs), or through noncompetitive inhibition of the pyrophosphate binding site (pyrophosphate analogs).