Increased human cytomegalovirus replication in fibroblasts after treatment with therapeutical plasma concentrations of valproic acid

Valproic acid (2-propylpentanoic acid, VPA), an effective inhibitor of histone deacetylases (HDAC) is used for the treatment of epilepsia. In this study, structure–activity relationships for the action of structurally modified VPA derivatives on human cytomegalovirus (HCMV) replication and HDAC inhi...

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Bibliographic Details
Published in:Biochemical pharmacology 2004-08, Vol.68 (3), p.531-538
Main Authors: Michaelis, Martin, Köhler, Nezira, Reinisch, Alexander, Eikel, Daniel, Gravemann, Ute, Doerr, Hans Wilhelm, Nau, Heinz, Cinatl, Jindrich
Format: Article
Language:English
Subjects:
Acetylation
Anticonvulsants - pharmacology
Biological and medical sciences
Cells, Cultured
Cytomegalovirus - drug effects
Cytomegalovirus - physiology
Dose-Response Relationship, Drug
Fibroblasts - drug effects
Fibroblasts - virology
Gene Expression Regulation, Viral - drug effects
Genes, Immediate-Early - drug effects
Histone deacetylases
Histones - metabolism
Human cytomegalovirus
Humans
Medical sciences
Pharmacology. Drug treatments
Structure–activity relationship
Teratogenicity
Time Factors
Transcription, Genetic - drug effects
Valproic acid
Valproic Acid - pharmacology
Virus Replication - drug effects
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Summary:Valproic acid (2-propylpentanoic acid, VPA), an effective inhibitor of histone deacetylases (HDAC) is used for the treatment of epilepsia. In this study, structure–activity relationships for the action of structurally modified VPA derivatives on human cytomegalovirus (HCMV) replication and HDAC inhibition were defined. Pretreatment of human foreskin fibroblasts with VPA (0.125–1 mM) caused a concentration-dependent increase of HCMV immediate early and antigen late antigen expression. Structure–activity relationships of VPA derivatives for HCMV stimulation were compared to those for teratogenic action and those for HDAC inhibition. Side chain elongation and introduction of a triple bond in 4-position of the other chain caused teratogenicity, stimulated HCMV replication, and increased HDAC inhibition, as demonstrated by enhanced levels of acetylated histones. Teratogenic VPA derivatives with a branched chain in 3-position as well as a non-teratogenic anticonvulsive active VPA derivative did not stimulate HCMV or accumulation of acetylated histones. This demonstrates a strict correlation between inhibition of HDAC and increased HCMV replication.
ISSN:0006-2952
1873-2968
DOI:10.1016/j.bcp.2004.04.013