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  • Title: Increased human cytomegalovirus replication in fibroblasts after treatment with therapeutical plasma concentrations of valproic acid.
    Author: Michaelis M, Köhler N, Reinisch A, Eikel D, Gravemann U, Doerr HW, Nau H, Cinatl J.
    Journal: Biochem Pharmacol; 2004 Aug 01; 68(3):531-8. PubMed ID: 15242819.
    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.
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