Some epigenetic pharmaceuticals have
the potential to be used as broad spectrum antivirals, according to a new
study. The study demonstrated that histone methyltransferases EZH2/1
inhibitors, which are being used in cancer clinical trials, have activity
against a variety of viruses, including herpes simplex virus (HSV).
Many DNA viruses, including HSV, are
subject to epigenetic regulation where productive infection, persistence, and
latency are determined, in part, by the modulation of chromatin associated with
viral genomes. For a number of years, research laboratories including that of
Thomas Kristie, PhD, a principal investigator in the Laboratory of Viral
Diseases, National Institute of Allergy and Infectious Diseases, have focused
on studying the epigenetic regulation of HSV. The virus impacts a significant
proportion of the world's population, and primary infection and subsequent
recurrent reactivation can result in disease ranging from mild lesions to
severe ocular or neurological damage.
EZH2/1 are histone-lysine
N-methyltransferase enzymes that are epigenetic repressors that suppress gene
transcription via propagation of repressive H3K27me3 enriched chromatin
domains. Currently, multiple EZH2/1 inhibitors are being developed and
evaluated in cancer clinical trials. "Some specific cancers are based on
"gain of function" mutations in EZH2. Additionally, it has been
proposed that in some cancers, these enzymes repress anti-oncogenes and
treatment with EZH2/1 inhibitors might result in re-expression of these
anti-oncogenes." said Dr. Kristie.
In the new study, researchers
evaluated the impact of a series of these EZH2/1 inhibitors on HSV. Given that
EZH2/EZH1 has been implicated in repression of herpesvirus gene expression, the
researchers expected to see induction of viral gene expression. However, they
found instead that the inhibitors resulted in reduced HSV gene expression and
lytic infection in vitro and in vivo.
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Posted by Dr. Tim Sandle