Preclinical Screening Platform Identifies Azatadine-Dimaleate as a Potent Repurposed Therapeutic Against SARS-CoV-2...

Area of Science:

• Virology
• Drug Discovery
• Immunology

Background:

• SARS-CoV-2 emergence necessitates novel antiviral therapeutics due to evolving variants and vaccine limitations.
• Drug repurposing provides an efficient strategy to identify safe and effective treatments.

Purpose of the Study:

• To identify and validate potential SARS-CoV-2 therapeutics through a multi-tiered screening approach.
• To evaluate the efficacy of Azatadine-Dimaleate as an antiviral agent against SARS-CoV-2.

Main Methods:

• Screened 2,570 compounds in vitro, followed by ex vivo validation in human bronchial epithelial cells (WD-PBECs).
• Conducted in vivo assessment using the K18-hACE2 transgenic mouse model.
• Assessed viral replication, inflammatory gene expression, and combination therapy with Remdesivir.

Main Results:

• Azatadine-Dimaleate demonstrated potent antiviral activity (EC50: 4.0 µM) and significantly reduced viral replication in cell cultures.
• Reduced viral titers and inflammatory markers in WD-PBECs and K18-hACE2 mice, showing decreased weight loss and viral loads.
• Synergistic antiviral effects observed when combined with Remdesivir, enhancing efficacy and reducing drug concentrations needed.

Conclusions:

• Azatadine-Dimaleate is a highly effective antiviral candidate against SARS-CoV-2, maintaining efficacy across in vitro, ex vivo, and in vivo models.
• Supports clinical evaluation of Azatadine-Dimaleate, alone or with Remdesivir, for treating SARS-CoV-2 infections, including against emerging variants.