Mood stabilizers inhibit cytomegalovirus infection

Abstract

Cytomegalovirus (CMV) infection can generate debilitating disease in immunocompromised individuals and neonates. It is also the most common infectious cause of congenital birth defects in infected fetuses. Available anti-CMV drugs are partially effective but are limited by some toxicity, potential viral resistance, and are not recommended for fetal exposure. Valproate, valpromide, and valnoctamide have been used for many years to treat epilepsy and mood disorders. We report for the first time that, in contrast to the virus-enhancing actions of valproate, valpromide and valnoctamide evoke a substantial and specific inhibition of mouse and human CMV in vitro. In vivo, both drugs safely attenuate mouse CMV, improving survival, body weight, and developmental maturation of infected newborns. The compounds act by a novel mechanism that interferes with CMV attachment to the cell. Our work provides a novel potential direction for CMV therapeutics through repositioning of agents already approved for use in psychiatric disorders.

Clinical Infections by Herpesviruses in Patients Treated with Valproic Acid: A Nested Case-Control Study in the Spanish Primary Care Database, BIFAP

“…The results of our epidemiological study are consistent, and extend to humans, with previous reports on the in vivo potential of VPA and its derivative valpromide—which lacks the free carboxylic group and the HADC inhibitory activity—to interfere with herpesvirus multiplication in mice [7]. Hence, a trend to a protective effect in human patients was observed for both compounds, although the decreased risk observed was marginally significant only for VPA ( p = 0.053).…”

“…These results are consistent with in vitro studies showing that, in cultured cells, VPA inhibits the production of infectious progeny of different enveloped viruses causing relevant human and veterinary diseases [3,5,6,9,16,17] including herpesviruses [4,7,8].…”

“…VPA and related substances with licensed products in Spain are valproate sodium and valpromide. In vitro studies have shown that VPA inhibits the production of infectious progeny of a broad spectrum of enveloped viruses causing human and veterinary diseases, which likely reflects a VPA-mediated impairment of lipid metabolism that may affect different steps of a virus life cycle [3,4,5,6,7,8,9].…”

Inhibition of Epstein-Barr Virus Lytic Reactivation by the Atypical Antipsychotic Drug Clozapine

“…Clozapine had no significant effect on the transcription of HERVs in three types of brain cell lines, though VPA upregulated the transcription of many HERVs [44]. Valpromide, an anti-epileptic drug that inhibits EBV lytic reactivation [5], had no effect on vesicular stomatitis virus infection [45]. Valpromide and a structurally-related molecule valnoctamide inhibited infection and replication of the human herpesvirus cytomegalovirus in cell culture, and increased the survival rate of mice infected with mouse cytomegalovirus [45].…”

Valproic Acid and Its Amidic Derivatives as New Antivirals against Alphaherpesviruses

“…As mentioned previously, VPA affects lipid metabolism (including the synthesis of phosphatidylinositols) and formation of cell membranes, so it may alter the viral acquisition of lipid envelope, resulting in mature viral particles with low stability [45]. Furthermore, some studies have reported antiviral activity of VPA, VCD and VPD against cytomegalovirus (CMV), a virus belonging to the Herpesviridae family that causes brain defects in neonates, not only outside the central nervous system but also in the developing brain of rodents [65,69]. CMV attaches to the cell through interaction of its glycoprotein gB with cellular heparan sulfate proteoglycans, and both VCD and VPD appear to affect the recognition of gB [49,69].…”