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 inhibition were defined. Pretreatment of human foreskin fibroblasts with VPA (0.125-1mM) 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.
Michaelis
Martin
M
Institut für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Paul Ehrlich-Strasse 40, 60596 Frankfurt am Main, Germany.
Köhler
Nezira
N
Reinisch
Alexander
A
Eikel
Daniel
D
Gravemann
Ute
U
Doerr
Hans Wilhelm
HW
Nau
Heinz
H
Cinatl
Jindrich
J
D000107:Acetylation; D000927:Anticonvulsants / Q000494:pharmacology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000821:virology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014635:Valproic Acid / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D000927:Anticonvulsants; D006657:Histones; D014635:Valproic Acid