Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase

Scott H. James, Caroll B. Hartline, Emma A. Harden, Elizabeth M. Driebe, James M. Schupp, David M. Engelthaler, Paul S Keim, Terry L. Bowlin, Earl R. Kern, Mark N. Prichard

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Cyclopropavir (CPV) is active against human cytomegalovirus (CMV), as well as both variants of human herpesvirus 6 and human herpesvirus 8. The mechanism of action of CPV against CMV is similar to that of ganciclovir (GCV) in that it is phosphorylated initially by the CMV UL97 kinase, resulting in inhibition of viral DNA synthesis. Resistance to CPV maps to the UL97 kinase but is associated primarily with H520Q mutations and thus retains good antiviral activity against most GCV-resistant isolates. An examination of CMV-infected cultures treated with CPV revealed unusual cell morphology typically associated with the absence of UL97 kinase activity. A surrogate assay for UL97 kinase activity confirmed that CPV inhibited the activity of this enzyme and that its action was similar to the inhibition seen with maribavir (MBV) in this assay. Combination studies using real-time PCR indicated that, like MBV, CPV also antagonized the efficacy of GCV and were consistent with the observed inhibition of the UL97 kinase. Deep sequencing of CPV-resistant laboratory isolates identified a frameshift mutation in UL27, presumably to compensate for a loss of UL97 enzymatic activity. We conclude that the mechanism of action of CPV against CMV is complex and involves both the inhibition of DNA synthesis and the inhibition of the normal activity of the UL97 kinase.

Original languageEnglish (US)
Pages (from-to)4682-4691
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume55
Issue number10
DOIs
StatePublished - Oct 2011

Fingerprint

Cytomegalovirus
Phosphotransferases
Ganciclovir
Human Herpesvirus 6
High-Throughput Nucleotide Sequencing
Human Herpesvirus 8
Frameshift Mutation
cyclopropavir
Viral DNA
Antiviral Agents
Real-Time Polymerase Chain Reaction
Mutation
DNA
Enzymes

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

James, S. H., Hartline, C. B., Harden, E. A., Driebe, E. M., Schupp, J. M., Engelthaler, D. M., ... Prichard, M. N. (2011). Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase. Antimicrobial Agents and Chemotherapy, 55(10), 4682-4691. https://doi.org/10.1128/AAC.00571-11

Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase. / James, Scott H.; Hartline, Caroll B.; Harden, Emma A.; Driebe, Elizabeth M.; Schupp, James M.; Engelthaler, David M.; Keim, Paul S; Bowlin, Terry L.; Kern, Earl R.; Prichard, Mark N.

In: Antimicrobial Agents and Chemotherapy, Vol. 55, No. 10, 10.2011, p. 4682-4691.

Research output: Contribution to journalArticle

James, SH, Hartline, CB, Harden, EA, Driebe, EM, Schupp, JM, Engelthaler, DM, Keim, PS, Bowlin, TL, Kern, ER & Prichard, MN 2011, 'Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase', Antimicrobial Agents and Chemotherapy, vol. 55, no. 10, pp. 4682-4691. https://doi.org/10.1128/AAC.00571-11
James SH, Hartline CB, Harden EA, Driebe EM, Schupp JM, Engelthaler DM et al. Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase. Antimicrobial Agents and Chemotherapy. 2011 Oct;55(10):4682-4691. https://doi.org/10.1128/AAC.00571-11
James, Scott H. ; Hartline, Caroll B. ; Harden, Emma A. ; Driebe, Elizabeth M. ; Schupp, James M. ; Engelthaler, David M. ; Keim, Paul S ; Bowlin, Terry L. ; Kern, Earl R. ; Prichard, Mark N. / Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase. In: Antimicrobial Agents and Chemotherapy. 2011 ; Vol. 55, No. 10. pp. 4682-4691.
@article{45d3f96fc9d1422e8540194c683f9034,
title = "Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase",
abstract = "Cyclopropavir (CPV) is active against human cytomegalovirus (CMV), as well as both variants of human herpesvirus 6 and human herpesvirus 8. The mechanism of action of CPV against CMV is similar to that of ganciclovir (GCV) in that it is phosphorylated initially by the CMV UL97 kinase, resulting in inhibition of viral DNA synthesis. Resistance to CPV maps to the UL97 kinase but is associated primarily with H520Q mutations and thus retains good antiviral activity against most GCV-resistant isolates. An examination of CMV-infected cultures treated with CPV revealed unusual cell morphology typically associated with the absence of UL97 kinase activity. A surrogate assay for UL97 kinase activity confirmed that CPV inhibited the activity of this enzyme and that its action was similar to the inhibition seen with maribavir (MBV) in this assay. Combination studies using real-time PCR indicated that, like MBV, CPV also antagonized the efficacy of GCV and were consistent with the observed inhibition of the UL97 kinase. Deep sequencing of CPV-resistant laboratory isolates identified a frameshift mutation in UL27, presumably to compensate for a loss of UL97 enzymatic activity. We conclude that the mechanism of action of CPV against CMV is complex and involves both the inhibition of DNA synthesis and the inhibition of the normal activity of the UL97 kinase.",
author = "James, {Scott H.} and Hartline, {Caroll B.} and Harden, {Emma A.} and Driebe, {Elizabeth M.} and Schupp, {James M.} and Engelthaler, {David M.} and Keim, {Paul S} and Bowlin, {Terry L.} and Kern, {Earl R.} and Prichard, {Mark N.}",
year = "2011",
month = "10",
doi = "10.1128/AAC.00571-11",
language = "English (US)",
volume = "55",
pages = "4682--4691",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "10",

}

TY - JOUR

T1 - Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase

AU - James, Scott H.

AU - Hartline, Caroll B.

AU - Harden, Emma A.

AU - Driebe, Elizabeth M.

AU - Schupp, James M.

AU - Engelthaler, David M.

AU - Keim, Paul S

AU - Bowlin, Terry L.

AU - Kern, Earl R.

AU - Prichard, Mark N.

PY - 2011/10

Y1 - 2011/10

N2 - Cyclopropavir (CPV) is active against human cytomegalovirus (CMV), as well as both variants of human herpesvirus 6 and human herpesvirus 8. The mechanism of action of CPV against CMV is similar to that of ganciclovir (GCV) in that it is phosphorylated initially by the CMV UL97 kinase, resulting in inhibition of viral DNA synthesis. Resistance to CPV maps to the UL97 kinase but is associated primarily with H520Q mutations and thus retains good antiviral activity against most GCV-resistant isolates. An examination of CMV-infected cultures treated with CPV revealed unusual cell morphology typically associated with the absence of UL97 kinase activity. A surrogate assay for UL97 kinase activity confirmed that CPV inhibited the activity of this enzyme and that its action was similar to the inhibition seen with maribavir (MBV) in this assay. Combination studies using real-time PCR indicated that, like MBV, CPV also antagonized the efficacy of GCV and were consistent with the observed inhibition of the UL97 kinase. Deep sequencing of CPV-resistant laboratory isolates identified a frameshift mutation in UL27, presumably to compensate for a loss of UL97 enzymatic activity. We conclude that the mechanism of action of CPV against CMV is complex and involves both the inhibition of DNA synthesis and the inhibition of the normal activity of the UL97 kinase.

AB - Cyclopropavir (CPV) is active against human cytomegalovirus (CMV), as well as both variants of human herpesvirus 6 and human herpesvirus 8. The mechanism of action of CPV against CMV is similar to that of ganciclovir (GCV) in that it is phosphorylated initially by the CMV UL97 kinase, resulting in inhibition of viral DNA synthesis. Resistance to CPV maps to the UL97 kinase but is associated primarily with H520Q mutations and thus retains good antiviral activity against most GCV-resistant isolates. An examination of CMV-infected cultures treated with CPV revealed unusual cell morphology typically associated with the absence of UL97 kinase activity. A surrogate assay for UL97 kinase activity confirmed that CPV inhibited the activity of this enzyme and that its action was similar to the inhibition seen with maribavir (MBV) in this assay. Combination studies using real-time PCR indicated that, like MBV, CPV also antagonized the efficacy of GCV and were consistent with the observed inhibition of the UL97 kinase. Deep sequencing of CPV-resistant laboratory isolates identified a frameshift mutation in UL27, presumably to compensate for a loss of UL97 enzymatic activity. We conclude that the mechanism of action of CPV against CMV is complex and involves both the inhibition of DNA synthesis and the inhibition of the normal activity of the UL97 kinase.

UR - http://www.scopus.com/inward/record.url?scp=80052869461&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052869461&partnerID=8YFLogxK

U2 - 10.1128/AAC.00571-11

DO - 10.1128/AAC.00571-11

M3 - Article

C2 - 21788463

AN - SCOPUS:80052869461

VL - 55

SP - 4682

EP - 4691

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 10

ER -