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.
authors.affiliation: University of Alabama at Birmingham, Department of Pediatrics, 128 Children's Harbor Building, 1600 6th Avenue South, Birmingham, AL 35233-1711, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: James
authors.forename: Caroll B
authors.initials: CB
authors.lastname: Hartline
authors.forename: Emma A
authors.initials: EA
authors.lastname: Harden
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Driebe
authors.forename: James M
authors.initials: JM
authors.lastname: Schupp
authors.forename: David M
authors.initials: DM
authors.lastname: Engelthaler
authors.forename: Paul S
authors.initials: PS
authors.lastname: Keim
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: Mark N
authors.initials: MN
authors.lastname: Prichard
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003521:Cyclopropanes / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification; D004279:DNA, Viral / Q000096:biosynthesis; D024882:Drug Resistance, Viral / Q000235:genetics; D016368:Frameshift Mutation; D015774:Ganciclovir / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015654:Herpesvirus 6, Human / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D003521:Cyclopropanes; D004279:DNA, Viral; D015774:Ganciclovir; D006147:Guanine; D017853:Phosphotransferases (Alcohol Group Acceptor); D012263:Ribonucleosides; C495219:cyclopropavir; C075365:ganciclovir kinase; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole