title: Phenotypic characterization of two naturally occurring human Cytomegalovirus sequence polymorphisms located in a distinct region of ORF UL56 known to be involved in in vitro resistance to letermovir.
abstract: Letermovir is a new drug in Phase 3 clinical development for the prevention of human Cytomegalovirus (HCMV) infections in hematopoietic-stem-cell transplant recipients (HSCT). In contrast to marketed anti-HCMV drugs which all target the viral DNA polymerase, letermovir's novel mode of action targets the UL56 subunit of the viral terminase complex. Consistently letermovir resistance has mapped in vitro to a distinct region within ORF UL56 (amino acid 230-370). Here we used marker transfer to demonstrate that two naturally occurring UL56 sequence variants within this region, located directly adjacent to sites known to mediate letermovir resistance in vitro (D242G and A327V) represent normal interstrain polymorphisms unrelated to drug-resistance.
authors: AiCuris GmbH & Co. KG, Friedrich Ebert-Str.475, 42117 Wuppertal, Germany.
authors: Thomas
authors: T
authors: Goldner
authors: AiCuris GmbH & Co. KG, Friedrich Ebert-Str.475, 42117 Wuppertal, Germany.
authors: Holger
authors: H
authors: Zimmermann
authors: AiCuris GmbH & Co. KG, Friedrich Ebert-Str.475, 42117 Wuppertal, Germany. Electronic address: peter.lischka@aicuris.com.
authors: Peter
authors: P
authors: Lischka
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000188:drug therapy* / Q000821:virology; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009154:Mutation; D016366:Open Reading Frames; D010641:Phenotype; D011110:Polymorphism, Genetic; D011799:Quinazolines / Q000494:pharmacology*; D015678:Viral Structural Proteins / Q000235:genetics*
chemical_list: D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C090238:UL56 protein, cytomegalovirus; D015678:Viral Structural Proteins; C000588473:letermovir
keywords: AIC246; Antiviral drugs; Cytomegalovirus; HCMV; Letermovir; MK-8228