ArticleAntimicrobial agents and chemotherapy2015
Rapid In Vitro Evolution of Human Cytomegalovirus UL56 Mutations That Confer Letermovir Resistance.
Article in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed.
- Comparative Emergence of Maribavir and Ganciclovir Resistance in a Randomized Phase 3 Clinical Trial for Treatment of Cytomegalovirus Infection.The Journal of infectious diseases · 2025Trial
- Drug Resistance Assessed in a Phase 3 Clinical Trial of Maribavir Therapy for Refractory or Resistant Cytomegalovirus Infection in Transplant Recipients.The Journal of infectious diseases · 2024Trial
- Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial.Annals of internal medicine · 2020Trial
- Something old, something new? Herpesvirus genome packaging examined in light of lessons from the tailed bacteriophages.Journal of virology · 2026Review
- A novel inhibitor of human cytomegalovirus acts through a specific antiviral mechanism that involves the helicase-primase complex.Antimicrobial agents and chemotherapy · 2026Article
- Viral Nuclease Inhibitors: Small molecule disruptors of the UL12 alkaline nuclease display broad anti-herpes virus activity.PLoS pathogens · 2026Article
- Mapping the monoclonal antibody landscape of human cytomegalovirus.Journal of virology · 2026Review
- Article
- Viral Nuclease Inhibitors: Small molecule disruptors of the UL12 alkaline nuclease display broad anti-herpes virus activity.bioRxiv : the preprint server for biology · 2026Article
- Computational Investigation of Novel pUL56 Ligands Using Docking and Molecular Dynamics with Preliminary Cytotoxicity Evaluation: An Early-Stage Study.Molecules (Basel, Switzerland) · 2026Article
- The HCMV terminase as an antiviral target: structural insights, inhibitory mechanisms, and the era of letermovir.Frontiers in microbiology · 2026Review
- Changing scenario in prevention and management of CMV infections in pediatric hematopoietic stem cell transplant patients.Bone marrow transplantation · 2026Review
- Safety signals and CMV-related events reported during letermovir therapy: a FAERS database study.Frontiers in pharmacology · 2026Article
- Key domains involved in the interaction and assembly of the HCMV terminase complex.Scientific reports · 2025Article
- Functional and structural insights into HCMV terminase accessory proteins pUL77 and pUL93.Journal of virology · 2025Article
- Identification of a binding pocket of letermovir in the terminase subunit pUL56 of human cytomegalovirus.Scientific reports · 2025Article
- Letermovir Treatment for Refractory or Resistant Cytomegalovirus Infection or Disease or with Concurrent Organ Dysfunction: A Phase 2 Open Label Study.Journal of the Association of Medical Microbiology and Infectious Disease Canada = Journal officiel de l'Association pour la microbiologie medicale et l'infectiologie Canada · 2025Article
- Letermovir for Prevention of Recurrent Cytomegalovirus in High-Risk Allogeneic Hematopoietic Cell Transplantation Recipients.Transplantation and cellular therapy · 2025Article
- HerpesDRG: a comprehensive resource for human herpesvirus antiviral drug resistance genotyping.BMC bioinformatics · 2024Article
- Phenotypes of cytomegalovirus genetic variants encountered in a letermovir clinical trial illustrate the importance of genotyping validation.Antiviral research · 2024Article
33 more citing papers are in PubMed but not listed here.
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Funding
Abstract
Letermovir (LMV) is an experimental cytomegalovirus terminase inhibitor undergoing phase 3 clinical trials. Viral mutations have been described at UL56 codons 231 to 369 that confer widely variable levels of LMV resistance. In this study, 15 independent experiments propagating an exonuclease mutant viral strain in escalating LMV concentrations replicated 6 of the 7 published UL56 mutations and commonly elicited additional resistance-conferring mutations at UL56 codons 231, 236, 237, 244, 257, 261, 325, and 329. Mutations were first detected earlier in LMV (median, 3 passages) than in 8 parallel experiments with foscarnet (median, 15 passages). As LMV concentrations increased, the typical initial UL56 change F261L, which confers low-grade resistance, combined or was replaced with mutations conferring higher-grade resistance, eventually enabling normal viral growth in 30 μM LMV (>5,000-fold the 50% effective concentration [EC50] for the wild type). At high LMV concentrations, the UL56 changes C325F/R were commonly detected, as well as a combination of changes at codons 236, 257, 329, and/or 369. Recombinant viruses containing individual UL56 mutations and combinations were constructed to confirm their resistance phenotypes and normal growth in cell culture. Several double and triple mutants showed much higher LMV resistance than the respective single mutants, particularly those including changes at both codons 236 and 257. The multiplicity of pathways to high-grade LMV resistance with minimal viral growth impact suggests a low viral genetic barrier and the need for close monitoring during treatment of active infection.
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