Antiviral Properties of the LSD1 Inhibitor SP-2509

Area of Science:

• Virology
• Molecular Biology
• Epigenetics

Background:

• Lysine-specific demethylase 1 (LSD1) regulates gene expression and DNA replication, and is essential for herpes simplex virus 1 (HSV-1) replication and latency.
• Previous studies suggest LSD1 interacts with HSV-1 replication forks, indicating a direct role in viral replication.
• LSD1 inhibitors like tranylcypromine (TCP) and OG-L002 target its demethylase activity, while SP-2509 inhibits protein-protein interactions.

Purpose of the Study:

• To investigate the effects of the LSD1 inhibitor SP-2509 on the HSV-1 life cycle.
• To determine if SP-2509 affects HSV-1 immediate early (IE) gene expression, DNA replication, or virus production.

Main Methods:

• Treatment of HSV-1-infected cells with SP-2509.
• Analysis of HSV-1 IE gene expression, transcription factor and RNA polymerase II (Pol II) association with viral DNA.
• EdC labeling of nascent viral DNA to visualize replication compartments.
• Assessment of viral DNA replication, late gene expression, and virus production.

Main Results:

• SP-2509 did not inhibit HSV-1 IE gene expression or early transcription factor/Pol II association with viral DNA.
• SP-2509 significantly inhibited HSV-1 DNA replication, late gene expression, and virus production.
• SP-2509 treatment led to the formation of aberrant viral replication compartments defective for Pol II recruitment.

Conclusions:

• LSD1 plays a crucial role in regulating HSV-1 DNA replication and gene expression after replication onset.
• SP-2509 effectively inhibits HSV-1 replication by disrupting these later stages of the viral life cycle.
• LSD1 inhibition represents a promising antiviral strategy against HSV-1.