Prevention and Treatment of Herpes Virus Infection by Inhibition of the JMJD2 Family of Histone Demethylases

Investigators at the NIH have discovered a potential means for preventing or treating a herpes virus infection by inhibiting the activity of the host cell’s histone demethylases. When herpesviruses enter a cell, they are inactivated by cellular defense mechanisms that wrap the viral genome in repressive chromatin structures. In order for viral replication to progress, the host’s own histone demethylases are recruited to the viral genome to reverse this repression. In a preceding invention, the laboratory disclosed that viral replication and reactivation can be significantly reduced through inhibition of the histone demethylase LSD1 using Mono-Amino Oxidase Inhibitors (MAOIs); drugs that are in clinical use. The current invention further discloses that inhibition of a second set of histone demethylases (JMJD2 family) using a specific JMJD2 inhibitor, dimethyloxaloylglycine (DMOG), also results in significant repression of herpes viral replication.

Either alone or in combination, small molecule inhibition of LSD1 and the JMJD2 family present novel approaches for preventing herpes virus infection and halting viral reactivation that can lead to a disease that ranges from mild core sores to herpesvirus keratitis and life threatening encephalitis. Additionally, chromatin-mediated repression of viral genomes and the requirement to de-repress these genomes for productive infection appears to be general to herpesviruses. Therefore, this treatment could also be applicable to chicken pox, shingles, CMV disease, mononucleosis, and Kaposi's sarcoma.