Optimizing drug discovery for snakebite envenoming via a high-throughput phospholipase A2 screening platform

Area of Science:

• Toxicology
• Drug Discovery
• Biochemistry

Background:

• Snakebite envenoming is a neglected tropical disease causing significant mortality.
• Current antivenoms have limitations, driving research into small molecule inhibitors for early intervention.
• Phospholipases A2 (PLA2) are key toxins in snake venoms, but effective inhibitors are scarce.

Purpose of the Study:

• To establish and optimize a high-throughput drug screening (HTS) assay for identifying novel PLA2 inhibitors.
• To screen a library of repurposed drugs against Russell's viper venom PLA2.
• To evaluate the broad-spectrum efficacy of identified inhibitors against various snake venoms.

Main Methods:

• Optimized a 384-well plate, colorimetric HTS assay for PLA2 inhibition.
• Screened approximately 3,500 post-phase I drugs against *Daboia russelii* venom.
• Determined drug efficacy and EC50 values against multiple snake venoms.

Main Results:

• Developed an efficient HTS assay with a throughput of ~2,800 drugs/day.
• Identified several novel PLA2 inhibitors from the repurposed drug library.
• Demonstrated broad-spectrum inhibitory potential of top hits against various snake venoms.

Conclusions:

• The developed HTS method is effective for discovering PLA2 inhibitors for snakebite treatment.
• Repurposed drugs represent a promising avenue for developing new snakebite interventions.
• Further exploration of chemical space using this method could yield valuable drugs to prevent snakebite envenoming pathology.