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Repurposing FDA-Approved Drugs as Potential Inhibitors of Feline Infectious Peritonitis Virus 3CLpro: An Integrated
Varanya Lueangaramkul1,2, Natjira Mana3, Nattarat Thangthamniyom3
1Graduate Program in Animal Health and Biomedical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand.
Abstract:
Feline infectious peritonitis (FIP), caused by feline coronavirus (FCoV) remains a critical therapeutic challenge with no universally approved treatments. We employed a drug repurposing strategy targeting the viral main protease (3CLpro), essential for FCoV replication. Virtual screening of FDA-approved drugs identified 15 candidates, with threesaquinavir (antiretroviral), lumacaftor (CFTR corrector), and gliquidone (antidiabetic)demonstrating notable antiviral activity. Postentry antiviral assays (cytopathic effect reduction, immunoperoxidase staining, RT-qPCR) yielded EC50 values of 0.25-0.48 μM (saquinavir), 30.32-58.49 μM (lumacaftor), and 48.85-51.28 μM (gliquidone). We validated 3CLpro inhibition using an intracellular dual-luciferase reporter assay designed to simultaneously account for compound cell penetration and metabolic stability. This confirmed specific protease inhibition with IC50 values of 23.70 ± 1.38 μM (saquinavir) and 38.68 ± 1.59 μM (lumacaftor), and 82.52 ± 1.50 μM (gliquidone). Synergy analysis with established anti-FIP agents (GC376, remdesivir, GS-441524, and molnupiravir) using SynergyFinder 3.0 revealed strong synergistic interactions: saquinavir + GC376 (mean ZIP score: 54.59), lumacaftor + GC376 (mean ZIP: 21.44), and gliquidone + remdesivir (mean ZIP: 24.13). Notably, optimal synergistic doses achieved 0.97-2.03 log10 viral suppression using only 20-50% of individual drug EC50 values, concurrently modulating viral-induced cytokine expression (TNF-α, IFN-β, and IL-6) in CRFK cells (p < 0.05). These rational combinations enable substantial dose reduction, offering practical strategies to improve treatment accessibility, reduce costs, and minimize adverse effects. This study establishes a framework for repurposing FDA-approved drugs in FIP therapy and supports translational evaluation of these combination regimens.
Insights
Repurposing FDA-approved drugs like saquinavir, lumacaftor, and gliquidone shows promise for treating Feline Infectious Peritonitis (FIP). Combining these drugs with existing antivirals significantly enhances efficacy and reduces required dosages.
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.
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