Liang, Yu (NIAID)
Vogel, Jodi (NIAID)
- Early-stage development
- Pre-clinical data available for mice
- Further pre-clinical and clinical development is needed
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.
Prevention or treatment of infection by herpes simplex virus and other diseases caused by herpesviruses (i.e. Epstein-Barr virus, cytomegalovirus, varicella zoster, and Kaposi's sarcoma-associated herpesvirus)
Inhibition of histone demethylases provides an alternative pathway for repressing herpes virus infection as compared to purine analog antivirals. While purine analogs are the most widely prescribed treatment for herpes infection, drug resistance is prevalent. Additionally, inhibition of histone demethylases results in no expression of viral gene products; in contrast to DNA replication inhibitors.