GPCR Inhibitors Have Antiviral Properties against JC Polyomavirus Infection.

Area of Science:

• Virology
• Neuroscience
• Pharmacology

Background:

• JC polyomavirus (JCPyV) establishes persistent kidney infections, reactivating under immunosuppression to cause fatal progressive multifocal leukoencephalopathy (PML).
• No approved therapies exist for PML, necessitating novel treatment strategies.

Purpose of the Study:

• To identify and validate antiviral compounds for JCPyV infection.
• To explore the mechanism of action for potential JCPyV inhibitors, focusing on G protein-coupled receptors (GPCRs) involved in viral entry.

Main Methods:

• Screening of receptor agonists/antagonists for antiviral activity against JCPyV.
• Validation of seven selected drugs using infectivity assays.
• Detailed mechanistic studies on GPCR-associated inhibitors, specifically 5-hydroxytryptamine 2 receptors (5-HT2Rs).

Main Results:

• Cetirizine and paroxetine demonstrated significant reduction in JCPyV infection early in the viral cycle.
• Paroxetine was shown to inhibit viral internalization by modulating 5-HT2C receptor density, reducing beta-arrestin recruitment, and decreasing ERK signaling.
• These findings implicate receptor signaling pathways in JCPyV entry.

Conclusions:

• Receptor signaling and viral entry mechanisms represent promising therapeutic targets for JCPyV infection.
• FDA-approved drugs targeting these receptors could potentially be repurposed as antivirals for treating JCPyV infection and PML.