Repurposing FDA-Approved Drugs as Potential Inhibitors of Feline Infectious Peritonitis Virus 3CL^pro: An Integrated...

Area of Science:

• Virology and Drug Discovery
• Antiviral Therapeutics
• Feline Infectious Peritonitis (FIP) Research

Background:

• Feline infectious peritonitis (FIP), caused by feline coronavirus (FCoV), presents a significant therapeutic challenge with no universally approved treatments.
• The viral main protease (3CLpro) is essential for FCoV replication, making it a key target for antiviral drug development.

Purpose of the Study:

• To identify FDA-approved drugs that can be repurposed to treat FIP by targeting the FCoV 3CLpro.
• To evaluate the antiviral activity and synergistic potential of repurposed drugs in combination with existing anti-FIP agents.

Main Methods:

• Virtual screening of FDA-approved drugs against FCoV 3CLpro.
• Antiviral assays including cytopathic effect reduction, immunoperoxidase staining, and RT-qPCR to determine EC50 values.
• Intracellular dual-luciferase reporter assay to confirm protease inhibition and assess compound stability.
• Synergy analysis using SynergyFinder 3.0 to evaluate drug combinations.

Main Results:

• Saquinavir, lumacaftor, and gliquidone demonstrated notable antiviral activity against FCoV.
• These drugs effectively inhibited FCoV 3CLpro with determined IC50 values.
• Significant synergistic interactions were observed between repurposed drugs and established anti-FIP agents (GC376, remdesivir), enabling substantial dose reduction and viral suppression.
• Combinations modulated viral-induced cytokine expression (TNF-α, IFN-β, IL-6).

Conclusions:

• Repurposing FDA-approved drugs offers a viable strategy for developing new FIP therapies.
• Rational drug combinations can significantly improve treatment accessibility, reduce costs, and minimize adverse effects.
• Further translational evaluation of these combination regimens is warranted for FIP treatment.