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

Goldner, Thomas; Zimmermann, Holger; Lischka, Peter

doi:10.1016/j.antiviral.2015.01.006

Cited by 26 publications

(13 citation statements)

References 22 publications

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“…For LMV, the UL56 codons 231 to 369, which include the most common resistance mutations, are distinct from the codon ranges (e.g., 425 to 476) where sequence polymorphisms are prevalent (30), and rare polymorphisms noted at codons 242 and 327 actually confer reduced LMV EC 50 s (31). Variation in cell culture conditions resulted in EC 50 s for maribavir that differed 100-fold for the same viral strain (32), but this was tested for LMV without finding a significant effect of cell type or viral inoculum (24).…”

Section: Discussionmentioning

confidence: 99%

RapidIn VitroEvolution of Human Cytomegalovirus UL56 Mutations That Confer Letermovir Resistance

Chou

2015

Antimicrob Agents Chemother

163

144

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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 M LMV (>5,000-fold the 50% effective concentration [EC 50 ] 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.T he prevention and treatment of human cytomegalovirus (CMV) infection and disease are an important aspect of the medical care of immunosuppressed individuals. The viral DNA polymerase inhibitors ganciclovir, its oral prodrug valganciclovir, foscarnet, and cidofovir have long been used for this purpose, with generally satisfactory outcomes but also well-known limitations of toxicity, intravenous treatment complexity, and risk of drug resistance after prolonged therapy (1). Cross-resistance among current drugs may develop because they have the same DNA polymerase target (2). Therefore, priority has been given to the development of alternative CMV drug targets. The viral terminase complex, including components encoded by the CMV genes UL56, UL89, and UL51, acting in concert with UL104 and others, is responsible for the cleavage of concatemeric DNA formed during viral replication into unit-length genomes and packaging them into preformed viral capsids (3). This essential process is an attractive target for specific viral inhibition. Drug discovery programs have identified diverse chemical structures that turned out to be CMV terminase inhibitors. Earlier candidates, a benzimidazole pyranoside GW275175X (4) and a chemically unrelated compound, Bay38-4766 (tomeglovir) (5), were tested in phase I trials but were not advanced to later-stage clinical development. Resistance mutations were mapped to the gen...

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Section: Discussionmentioning

confidence: 99%

RapidIn VitroEvolution of Human Cytomegalovirus UL56 Mutations That Confer Letermovir Resistance

Chou

2015

Antimicrob Agents Chemother

163

144

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“…The study is expected to complete the accrual in January 2017 for primary outcome (NCT02137772). Overall, in vitro LMV resistant CMV strains have been reported [79,80,81].…”

Section: Letermovir -The Terminasetormentioning

confidence: 99%

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

Madon

Giaccone

Festuccia

et al. 2016

Expert Review of Hematology

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“…Определены специфические мутации в открытой рамке считывания гена UL56, опосредующие резистентность к ЛТВ, и полученные данные подтверждают, что большая субъединица терминазы ЦМВ человека (рUL56) является биомишенью этого соединения. ЛТВ взаимодействует с рUL56 и ингибирует репродукцию ЦМВ, при этом не нарушается синтез дочерних вирусных ДНК и вирусных белков [50,51]. Интересно, что резистентные к ЛТВ варианты вируса сохраняют чувствительность к другим ингибиторам терминазы -BDCRB (2-бром-5,6-дихлор-1-β-D-рибофуранозилбензимидазолу), GW275175X (2-бром-5,6-дихлор-1-бета-D-рибопиранозил-1Н-бенз-(M460I, H520Q, C592G, C603R) и pUL54 (M844T, E756K, A809V), связанных с резистентностью к ГЦВ, приводящих к кросс-резистентности к ЦПВ.…”

Section: ингибиторы циклин-зависимой Ser/thr-киназы (Cdk) цмвunclassified

Modern Ethiotropic Chemotherapy of Human Cytomegalovirus Infection: Clinical Effectiveness, Molecular Mechanism of Action, Drug Resistance, New Trends and Prospects. Part 2

Андронова¹

2018

Problems of Virology

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A number of synthetic compounds, such as the nucleoside analog ganciclovir, its L-valine ester (a metabolic precursor of ganciclovir) and pyrophosphate analog foscarnet, are permitted for the treatment of HCMV-related diseases in the WHO European Region. The viral DNA- polymerase is used by all these drugs as a bio-target. However, the usage of standard anti-CMV therapy is accompanied by severe side effects, as well as the development of drug resistance in the virus, mainly in conditions of immunodeficiency. In this review, we focused on viral proteins of interest as new potential targets and their inhibitors, such as the inhibitor of human CMV terminology, lethermovir, which showed great activity in the third phase of clinical trials, inhibitors of viral cyclin-dependent kinase (maribavir, cyclopropavir ) and a number of compounds exhibiting anti-HCMV-activity, undergoing only preclinical trials in the experiment. Inclusion of new anti-CMV agents that are active against GСV/PFA/CDV-resistant strains of CMV into standard prophylactic and therapeutic regimens, will allow to increase the effectiveness of anti-CMV therapy, including in cases when standard therapy is ineffective. Areas covered: the international databases such as A MEDLINE, PubMed, eLIBRARY.RU, ClinicalTrials.gov., etc. with the purpose of obtaining information on compounds showing selective action against the human cytomegalovirus, the most promising for the development of drugs.

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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

Cited by 26 publications

References 22 publications

RapidIn VitroEvolution of Human Cytomegalovirus UL56 Mutations That Confer Letermovir Resistance

RapidIn VitroEvolution of Human Cytomegalovirus UL56 Mutations That Confer Letermovir Resistance

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

Modern Ethiotropic Chemotherapy of Human Cytomegalovirus Infection: Clinical Effectiveness, Molecular Mechanism of Action, Drug Resistance, New Trends and Prospects. Part 2

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