Thursday, 5 October 2017

Epigenetic drugs show promise as antivirals


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.

See:

Jesse H. Arbuckle, Paul J. Gardina, David N. Gordon, Heather D. Hickman, Jonathan W. Yewdell, Theodore C. Pierson, Timothy G. Myers, and Thomas M. Kristie. Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral PathogensmBio, July/August 2017 DOI: 10.1128/mBio.01141-17

Posted by Dr. Tim Sandle