PMID- 14698045
OWN - NLM
STAT- MEDLINE
DCOM- 20040211
LR  - 20211203
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 67
IP  - 2
DP  - 2004 Jan 15
TI  - Potent, selective and cell-mediated inhibition of human herpesvirus 6 at an early 
      stage of viral replication by the non-nucleoside compound CMV423.
PG  - 325-36
AB  - CMV423 (2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is a 
      new antiviral agent with potent and selective in vitro activity against the 
      beta-herpesvirus human cytomegalovirus (HCMV), but not against alpha- or 
      gamma-herpesviruses. Here we report that its activity also extends to human 
      herpesvirus 6 (HHV-6) and 7 (HHV-7). When compared in vitro to ganciclovir and 
      foscarnet (the standard drugs recommended for treatment of HHV-6 infections), 
      CMV423 showed a superior selectivity, due to its high activity (antiviral IC(50): 
      53nM) and low cytotoxicity (CC(50): 144microM), both in continuous cell lines and 
      in CBLCs infected with HHV-6. From mechanistic experiments at the level of viral 
      mRNA and protein expression, we learned that CMV423 targets an event following 
      viral entry but preceding viral DNA replication. Its antiviral action was 
      dependent on the cell line used, implying involvement of a cellular component. 
      When compared to a panel of known protein kinase inhibitors, CMV423 was found to 
      share anti-HHV-6 characteristics with herbimycin A, which affects tyrosine kinase 
      activity through heat shock protein 90 (Hsp90) inhibition. We demonstrated that 
      high concentrations of CMV423 have an inhibitory effect on the total cellular 
      protein tyrosine kinase activity, and that CMV423 and herbimycin A, when 
      combined, act synergistically against HHV-6. The activities of cyclin-dependent 
      kinases, protein kinases A and C, and the HHV-6-encoded pU69 kinase were not 
      affected. We, therefore, conclude that CMV423 exerts its activity against HHV-6 
      through inhibition of a cellular process that is critical at early stages of 
      viral replication and that may affect protein tyrosine kinase activity.
FAU - De Bolle, Leen
AU  - De Bolle L
AD  - Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000, 
      Leuven, Belgium.
FAU - Andrei, Graciela
AU  - Andrei G
FAU - Snoeck, Robert
AU  - Snoeck R
FAU - Zhang, Ying
AU  - Zhang Y
FAU - Van Lommel, Alfons
AU  - Van Lommel A
FAU - Otto, Michael
AU  - Otto M
FAU - Bousseau, Anne
AU  - Bousseau A
FAU - Roy, Christine
AU  - Roy C
FAU - De Clercq, Erik
AU  - De Clercq E
FAU - Naesens, Lieve
AU  - Naesens L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (2-chloro-3-pyridine-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide)
RN  - 0 (Antiviral Agents)
RN  - 0 (Carrier Proteins)
RN  - 0 (Indolizines)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Pyridines)
RN  - 0 (protein kinase modulator)
RN  - 364P9RVW4X (Foscarnet)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (pU69 kinase, human herpesvirus 6)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.7.7 (DNA-Directed DNA Polymerase)
RN  - P9G3CKZ4P5 (Ganciclovir)
SB  - IM
MH  - Antiviral Agents/*pharmacology
MH  - Carrier Proteins/metabolism
MH  - Cell Cycle/drug effects
MH  - DNA-Directed DNA Polymerase/metabolism
MH  - Foscarnet/pharmacology
MH  - Ganciclovir/pharmacology
MH  - Gene Expression/drug effects
MH  - Herpesvirus 6, Human/*drug effects/enzymology/physiology
MH  - Herpesvirus 7, Human/drug effects
MH  - Humans
MH  - Indolizines/*pharmacology
MH  - *Intracellular Signaling Peptides and Proteins
MH  - Microbial Sensitivity Tests
MH  - Phosphotransferases (Alcohol Group Acceptor)/metabolism
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors
MH  - Pyridines/*pharmacology
MH  - Transcription, Genetic/drug effects
MH  - Tumor Cells, Cultured
MH  - Virus Replication/*drug effects
EDAT- 2003/12/31 05:00
MHDA- 2004/02/12 05:00
CRDT- 2003/12/31 05:00
PHST- 2003/12/31 05:00 [pubmed]
PHST- 2004/02/12 05:00 [medline]
PHST- 2003/12/31 05:00 [entrez]
AID - S0006295203006683 [pii]
AID - 10.1016/j.bcp.2003.08.042 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2004 Jan 15;67(2):325-36. doi: 10.1016/j.bcp.2003.08.042.