A potential therapeutic strategy by fungal laccase targeting novel binding sites on human cytomegalovirus DNA polymerase.

Human cytomegalovirus (HCMV) is a common herpesvirus that can severely affect transplant recipients, those with AIDS, and newborns. Existing synthetic medications face limitations, including toxicity, processing issues, and viral resistance. As part of this study, the efficacy of the extracellular enzyme laccase isolated from a widely available mushroom (Pleurotus pulmonarius) was compared to that of ganciclovir, a common antiviral, used against HCMV. The study found that laccase can synergistically inhibit HCMV replication by targeting new inhibitory sites on the UL54 protein. Viral replication requires significant energy, increasing cellular respiration. The antiviral effect of laccase was linked to reduced expression of genes regulating cellular respiration, which coincided with decreased viral DNA copies. Additionally, in silico analysis has identified a novel binding site for the laccase enzyme in the C-terminal region of HCMV DNA polymerase specifically between amino acids 1004 and 1242, which effectively obstructs the binding of the essential viral replication regulatory accessory protein UL44, thereby hindering successful replication. Molecular dynamics simulations were performed under standardized conditions mimicking a cellular environment, revealing a stable protein-protein docking complex. This study may aid in developing novel antiviral strategies by utilizing laccase's target specificity to regulate host cellular pathways against Herpesviridae.