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

Biochemical Pharmacology
Martin MichaelisJindrich Cinatl

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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Citations

Oct 24, 2007·Apoptosis : an International Journal on Programmed Cell Death·Irina TretiakovaOliver Werz
Aug 31, 2010·Cellular and Molecular Life Sciences : CMLS·Martin MichaelisJindrich Cinatl
Jul 3, 2013·Joint, Bone, Spine : Revue Du Rhumatisme·Vincent Descamps, Sylvie Ranger-Rogez
Nov 3, 2010·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Martin MichaelisJindrich Cinatl
Sep 30, 2010·Virus Research·Matthew B Reeves
Sep 3, 2008·Journal of Ethnopharmacology·Chung-Jen ChenHans Wilhelm Doerr
Oct 13, 2006·Medical Hypotheses·Farhad F Shadan
Sep 23, 2016·Virology·Sara OrnaghiAnthony N van den Pol
Mar 5, 2016·MBio·Kelly L GorresGeorge Miller
Feb 24, 2021·Proceedings of the National Academy of Sciences of the United States of America·Ian J GrovesMark R Wills
Sep 1, 2021·Antiviral Chemistry & Chemotherapy·Wenxiao ZhengVishwajit L Nimgaonkar
Aug 31, 2021·Journal of the European Academy of Dermatology and Venereology : JEADV·B LargeauA-P Jonville-Béra

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