Letermovir is used for prophylaxis against cytomegalovirus (CMV) in allogeneic stem cell transplant recipients. Its mechanism of action is unique among antivirals. What is its target?
- A CMV-specific DNA polymerase UL54, competing with ganciclovir for the same active site
- B Viral capsid tegument protein pp65 preventing nuclear egress of CMV
- C Viral terminase complex (UL51, UL56, UL89 subunits) that cleaves viral DNA concatemers and packages it into procapsids; does not require activation by viral kinase UL97 ✓
- D Host cell CDK2, preventing G1/S transition required for CMV DNA replication
Explanation
Letermovir is an anti-CMV drug that uniquely targets the viral terminase complex — a heterotrimer of UL51, UL56, and UL89 proteins that cleavages viral DNA from concatemeric head-to-tail repeats and packages unit-length genomes into procapsids. This mechanism is completely distinct from ganciclovir, cidofovir, and foscarnet, which all target the viral DNA polymerase UL54. Critically, letermovir does NOT require phosphorylation by the viral kinase UL97 (which activates ganciclovir) — so letermovir retains activity against ganciclovir-resistant CMV with UL97 mutations. However, combination with ganciclovir for UL97-mutated CMV disease uses letermovir's distinct mechanism as a complement.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.