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

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

Research output: Contribution to journalArticle

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Abstract

Methylenecyclopropane nucleoside (MCPN) analogs are being investigated for treatment of human cytomegalovirus (HCMV) infection because of favorable preclinical data and limited ganciclovir cross-resistance. Monohydroxymethyl MCPNs bearing ether and thioether functionalities at the purine 6 position have antiviral activity against herpes simplex virus (HSV) and varicella-zoster virus (VZV) in addition to HCMV. The role of theHCMVUL97 kinase in the mechanism of action of these derivatives was examined. When tested against a kinase-inactive UL97 K355M virus, a moderate 5- to 7-fold increase in 50% effective concentration (EC50) was observed, in comparison to a 13- to 25-fold increase for either cyclopropavir or ganciclovir. Serial propagation ofHCMVunder two of these compounds selected for three novel UL97 mutations encoding amino acid substitutions D456N, C480R,and Y617del. When transferred to baseline laboratoryHCMVstrains, these mutations individually conferred resistance to all of the tested MCPNs, ganciclovir, and maribavir. However, the engineered strains also demonstrated severe growth defects and abnormal cytopathic effects similar to the kinase-inactive mutant. Expressed and purified UL97 kinase showed in vitro phosphorylation of the newly tested MCPNs. Thus,HCMVUL97 kinase is involved in the antiviral action of these MCPNs, but the in vitro selection of UL97-defective viruses suggests that their activity against more typical ganciclovir-resistant growth-competent UL97 mutants may be relatively preserved.

Original languageEnglish (US)
Pages (from-to)274-278
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number1
DOIs
StatePublished - Jan 2014

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Sulfides
Cytomegalovirus
Ganciclovir
Ether
Phosphotransferases
Antiviral Agents
Defective Viruses
Mutation
Human Herpesvirus 3
Cytomegalovirus Infections
Simplexvirus
Amino Acid Substitution
Growth
Nucleosides
Phosphorylation
methylenecyclopropane
Viruses
In Vitro Techniques

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

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.; Bowlina, Terry L.

In: Antimicrobial Agents and Chemotherapy, Vol. 58, No. 1, 01.2014, p. 274-278.

Research output: Contribution to journalArticle

Komazin-Meredith, G, Chou, S, Prichard, MN, Hartline, CB, Cardinale, SC, Comeau, K, Williams, JD, Khan, AR, Peet, NP & Bowlina, TL 2014, 'Human Cytomegalovirus UL97 Kinase Is Involved in the Mechanism of Action of Methylenecyclopropane Analogs with 6-Ether and -Thioether Substitutions', Antimicrobial Agents and Chemotherapy, vol. 58, no. 1, pp. 274-278. https://doi.org/10.1128/AAC.01726-13
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. ; Bowlina, Terry L. / Human Cytomegalovirus UL97 Kinase Is Involved in the Mechanism of Action of Methylenecyclopropane Analogs with 6-Ether and -Thioether Substitutions. In: Antimicrobial Agents and Chemotherapy. 2014 ; Vol. 58, No. 1. pp. 274-278.
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abstract = "Methylenecyclopropane nucleoside (MCPN) analogs are being investigated for treatment of human cytomegalovirus (HCMV) infection because of favorable preclinical data and limited ganciclovir cross-resistance. Monohydroxymethyl MCPNs bearing ether and thioether functionalities at the purine 6 position have antiviral activity against herpes simplex virus (HSV) and varicella-zoster virus (VZV) in addition to HCMV. The role of theHCMVUL97 kinase in the mechanism of action of these derivatives was examined. When tested against a kinase-inactive UL97 K355M virus, a moderate 5- to 7-fold increase in 50{\%} effective concentration (EC50) was observed, in comparison to a 13- to 25-fold increase for either cyclopropavir or ganciclovir. Serial propagation ofHCMVunder two of these compounds selected for three novel UL97 mutations encoding amino acid substitutions D456N, C480R,and Y617del. When transferred to baseline laboratoryHCMVstrains, these mutations individually conferred resistance to all of the tested MCPNs, ganciclovir, and maribavir. However, the engineered strains also demonstrated severe growth defects and abnormal cytopathic effects similar to the kinase-inactive mutant. Expressed and purified UL97 kinase showed in vitro phosphorylation of the newly tested MCPNs. Thus,HCMVUL97 kinase is involved in the antiviral action of these MCPNs, but the in vitro selection of UL97-defective viruses suggests that their activity against more typical ganciclovir-resistant growth-competent UL97 mutants may be relatively preserved.",
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AU - Cardinale, Steven C.

AU - Comeau, Katelyn

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