*4.5. E*ff*ect of Clozapine and Its Metabolites on Other Viruses*

The clozapine metabolite N-desmethylclozapine was found to inhibit replication of dengue virus (DENV) [41]. The inhibition of N-desmethylclozapine was specific to DENV. It did not have an effect on other flaviviruses (i.e., Japanese encephalitis virus, West Nile virus), or on the RNA viruses respiratory syncytial virus and rotavirus. Inhibition occurred at an early step in the viral life cycle prior to viral replication. Two other metabolites of clozapine, 8-OH-deschloro-clozapine and 8-OH-desmethylclozapine, inhibit human immunodeficiency virus (HIV) type 1 [42]. Neither clozapine, the primary compound, nor desmethylclozapine show any antiviral effects, suggesting that inhibition of HIV is due to the metabolism of clozapine. Clozapine (30 μM) decreased the infection of a human glial cell line by the human polyomavirus JC virus by approximately one-half [43]. The human endogenous retroviruses (HERVs) are associated with schizophrenia and other neurological diseases. 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].

In conclusion, the repurposing of antipsychotic drugs as antivirals has the potential for therapeutic use. Understanding how clozapine inhibits EBV may lead to the discovery of cellular pathways that regulate the latent–lytic switch of the virus. Future studies will be aimed at determining the effects of other antipsychotic drugs on EBV lytic reactivation and identifying common molecular targets in cells that may provide information about the mechanisms important in neurological disease and for the viral life cycle.

**Author Contributions:** K.L.G conceived the research and designed the experiments; A.G.A., C.B.G., and J.R.W. performed the experiments; K.L.G., A.G.A., and C.B.G. analyzed the data; K.L.G. did the statistical analysis; K.L.G., A.G.A., and J.R.W. wrote the paper; K.L.G. edited the paper.

**Acknowledgments:** We thank McKenna Theine, Jenna Hayes, and Kayla Feehan for technical assistance. This work was funded by the UWL College of Science and Health and UWL Faculty Research Grants to K.L.G., the UWL Eagle Apprentice Program for J.R.W., and UWL Undergraduate Research and Creativity grants to A.G.A. and C.B.G.

**Conflicts of Interest:** The authors declare no conflict of interest.

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