Human Cytomegalovirus UL97 Kinase Is Involved in the Mechanism of Action of Methylenecyclopropane Analogs with 6-Ether and -Thioether Substitutions

Komazin-Meredith, Gloria; Chou, Sunwen; Prichard, Mark N.; Hartline, Caroll B.; Cardinale, Steven C.; Comeau, Katelyn; Williams, John D.; Khan, Atiyya R.; Peet, Norton P.; Bowlin, Terry L.

doi:10.1128/aac.01726-13

Cited by 26 publications

(19 citation statements)

References 30 publications

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“…Mutations that knock out UL97 kinase activity, e.g. by altering a critical residue such as K355, are inherently highly resistant to maribavir and cross-resistant to ganciclovir, but have no demonstrated clinical relevance because of the resulting severe viral growth impairment [12,15]. This includes some of the mutants in Table 1 that show high-level maribavir resistance (>200-fold increased EC50).…”

Section: Genetic Mechanisms Of CMV Drug Resistancementioning

confidence: 99%

Approach to drug-resistant cytomegalovirus in transplant recipients

Chou

2015

Current Opinion in Infectious Diseases

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Purpose of review updated information on diagnosis of CMV drug resistance, treatments for drug-resistant infection and potential uses of experimental antiviral compounds. Recent findings For established CMV antivirals, uncommon viral UL97 kinase and UL54 DNA polymerase drug resistance mutations are sporadically described that expand an extensive existing database. Some novel mutations reported from treated patients have no drug resistant phenotype and may be genotyping artifacts. Next generation sequencing technology may enable earlier detection of emerging resistance mutations in treated patients. Management options for drug-resistant infection include optimization of host defenses, antiviral dose escalation, substitutions or combinations of standard or experimental antivirals. Maribavir and letermovir have antiviral targets distinct from the classic DNA polymerase. UL97 mutations elicited by ganciclovir and maribavir are different, although a single p-loop mutation can confer significant cross-resistance. High-grade resistance mutations in the UL56 terminase gene are readily selected in vitro under letermovir and await clinical correlation. Summary Technical advancements can enhance the accurate and timely genotypic detection of drug resistance. Antivirals undergoing clinical trial offer the prospect of new viral targets and drug combinations, but unresolved issues exist with regard to their therapeutic potential for drug-resistant CMV and their genetic barriers to resistance.

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Section: Genetic Mechanisms Of CMV Drug Resistancementioning

confidence: 99%

Approach to drug-resistant cytomegalovirus in transplant recipients

Chou

2015

Current Opinion in Infectious Diseases

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“…MBX 2168 is phosphorylated by UL97, a serine-threonine protein kinase encoded by HCMV and resistance to MBX 2168 maps to this viral kinase (Komazin-Meredith et al, 2014). MBX 2168 is also a substrate of the HHV-6 U69 protein kinase, which is a homologue of UL97 (Komazin-Meredith et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

“…The proposed mechanism of action of these compounds involves their sequential phosphorylation to a triphosphate, which then inhibits viral DNA polymerase. We previously showed that the HCMV protein kinase UL97 and the HHV-6 protein kinase U69 are involved in phosphorylation of MCPNs to their monophosphates (Komazin-Meredith et al, 2013; Komazin-Meredith et al, 2014). The antiviral activity of these compounds was, however, less dependent on the activity of the HCMV UL97 kinase than was CPV, suggesting the involvement of a host enzyme in their phosphorylation (Komazin-Meredith et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…We previously showed that the HCMV protein kinase UL97 and the HHV-6 protein kinase U69 are involved in phosphorylation of MCPNs to their monophosphates (Komazin-Meredith et al, 2013; Komazin-Meredith et al, 2014). The antiviral activity of these compounds was, however, less dependent on the activity of the HCMV UL97 kinase than was CPV, suggesting the involvement of a host enzyme in their phosphorylation (Komazin-Meredith et al, 2014). Unlike ACV, monohydroxymethyl MCPNs also do not require HSV TK for activity, which could be promising for treatment of ACV-resistant infections with resistance mapping to the viral TK (Prichard et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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TAOK3 phosphorylates the methylenecyclopropane nucleoside MBX 2168 to its monophosphate

et al. 2015

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Monohydroxymethyl methylenecyclopropane nucleosides (MCPNs) with ether or thioether substituents at the 6-position show promise as broad-spectrum herpes virus inhibitors. Their proposed mechanism of action involves sequential phosphorylation to a triphosphate, which can then inhibit viral DNA polymerase. The inhibition of herpes simplex virus (HSV) by these compounds is not dependent on the viral thymidine kinase (TK), which is known to phosphorylate acyclovir (ACV), a standard treatment for HSV infections. Previous studies on the mechanism of action of these compounds against human cytomegalovirus (HCMV) implicated a host kinase in addition to HCMV UL97 kinase in performing the initial phosphorylation. After first eliminating other candidate HSV-1 encoded kinases (UL13 and US3) as well as potential host nucleoside kinases, using activity-based fractionation, we have now identified the host serine-threonine protein kinase TAOK3 as the kinase responsible for transforming the representative monohydroxymethyl MCPN analog MBX 2168 to its monophosphate.

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“…Additionally, 6-alkoxy and 6-alkylthio derivatives of synguanol have been synthesized that showed improved in vitro antiviral activities against CMV and other herpesviruses (8). As with ganciclovir, the CMV UL97 kinase is involved in the initial phosphorylation of these compounds, and drug-resistant UL97 mutants have been described (9). The aim of the present study was to compare the activities of synguanol, a 6-ether derivative (MBX2168), a 6-thioether derivative (MBX1616), and cyclopropavir ( Fig.…”

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Cytomegalovirus Mutants Resistant to Ganciclovir and Cidofovir Differ in Susceptibilities to Synguanol and Its 6-Ether and 6-Thioether Derivatives

Chou

Komazin-Meredith

Williams

et al. 2014

Antimicrob Agents Chemother

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bThe methylenecyclopropane nucleoside (MCPN) analogs synguanol and its 6-alkoxy (MBX2168) and 6-alkylthio (MBX1616) derivatives retained good in vitro activities against several common ganciclovir-resistant UL97 kinase variants of human cytomegalovirus. Foscarnet-MCPN cross-resistance was observed among UL54 polymerase variants. UL54 exonuclease domain ganciclovir-cidofovir dual-resistant variants were remarkably more hypersensitive to these MCPNs than to cyclopropavir, with some 50% effective concentration ratios that were <0.1؋ the wild type. Different categories of MCPNs may have therapeutically exploitable mechanistic differences in viral DNA polymerase inhibition.

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Human Cytomegalovirus UL97 Kinase Is Involved in the Mechanism of Action of Methylenecyclopropane Analogs with 6-Ether and -Thioether Substitutions

Cited by 26 publications

References 30 publications

Approach to drug-resistant cytomegalovirus in transplant recipients

Approach to drug-resistant cytomegalovirus in transplant recipients

TAOK3 phosphorylates the methylenecyclopropane nucleoside MBX 2168 to its monophosphate

Cytomegalovirus Mutants Resistant to Ganciclovir and Cidofovir Differ in Susceptibilities to Synguanol and Its 6-Ether and 6-Thioether Derivatives

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