The HCMV terminase as an antiviral target: structural insights, inhibitory mechanisms, and the era of letermovir

Human cytomegalovirus (HCMV) remains a major cause of morbidity and mortality in immunocompromised individuals and newborns worldwide. Current antiviral therapies mainly target the viral DNA polymerase, but their long-term clinical use is often constrained by toxicity and the emergence of drug-resistant strains. The approval of letermovir, the first antiviral targeting the viral terminase complex, has established viral genome packaging as a highly effective therapeutic strategy. The HCMV terminase complex is essential for viral DNA cleavage and encapsidation and lacks direct human homologs, making it an attractive target for selective antiviral intervention. Accumulating evidence indicates that letermovir may primarily target pUL56, as resistance mutations cluster predominantly within this subunit. This review summarizes current understanding of the interaction between letermovir and the HCMV terminase, focusing on structural organization, inhibitory mechanisms, resistance mutations, and emerging approaches for next-generation inhibitor development, and highlighting key unresolved questions that will guide future structure-based antiviral discovery targeting herpesvirus genome packaging machinery.