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

Article Details

Citation

Michaelis M, Kohler N, Reinisch A, Eikel D, Gravemann U, Doerr HW, Nau H, Cinatl J Jr

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

Biochem Pharmacol. 2004 Aug 1;68(3):531-8.

PubMed ID
15242819 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Valproic acidHistone deacetylase 9ProteinHumans
Yes
Inhibitor
Details