DNA-directed DNA polymerase catalytic subunit (UL54) (UL54)

DNA-directed DNA polymerase catalytic subunit (UL54) is the essential enzyme responsible for replicating the human cytomegalovirus (HCMV) genome during the late phase of the viral life cycle (UniProt P08546). It functions as a member of the DNA polymerase family B, possessing both 5'-3' polymerase activity for DNA synthesis and 3'-5' exonuclease activity for proofreading (PubMed 8523551). To achieve high processivity, UL54 interacts with the accessory subunit UL44, forming a functional holoenzyme that produces long concatemeric DNA strands (PubMed 20538862). This enzyme is the primary therapeutic target for several approved antiviral drugs, including ganciclovir, foscarnet, and cidofovir (PubMed 32561611). These drugs act as nucleoside/nucleotide analogs or pyrophosphate analogs to halt viral replication by interfering with nucleotide incorporation or binding (PubMed 32561611). However, the emergence of mutations within the UL54 gene frequently leads to clinical drug resistance, posing a significant challenge in the management of HCMV infections (PubMed 32561611). This is particularly critical in immunocompromised patients, such as transplant recipients and those with HIV/AIDS, where HCMV can cause severe disease like retinitis or pneumonitis (PubMed 32561611). Current research also explores novel therapeutic strategies, such as small molecules like SGM8 that disrupt the protein-protein interaction between UL54 and its accessory subunit UL44 (PubMed 28440077).

Other names

UL54PolHFLF2DNA polymerase catalytic subunitpUL54DPOL_HCMVA

Inhibition of viral DNA synthesis through competitive inhibition of deoxyribonucleoside triphosphate (dNTP) binding, DNA chain termination upon incorporation, or blocking of the pyrophosphate binding site to prevent nucleotide incorporation.