A multiplex method for rapidly identifying viral protease inhibitors.

Area of Science:

• Virology
• Drug Discovery
• Biotechnology

Background:

• Existing antiviral treatments are insufficient against a wide range of pathogens and emerging viral threats.
• There is a critical need for accelerated discovery of novel antiviral therapeutics.
• Current drug screening methods are often slow and costly, hindering rapid response to viral outbreaks.

Purpose of the Study:

• To establish a high-throughput, multiplex screening platform for rapid identification of antiviral compounds.
• To discover broad-acting inhibitors targeting diverse viral proteases, including those from coronaviruses.
• To demonstrate the efficiency and cost-effectiveness of multiplex screening for drug discovery.

Main Methods:

• Development of a high-throughput platform screening over 100,000 compound-target interactions simultaneously against 40 viral proteases.
• Utilized cellular biosensors of viral protease activity combined with DNA-barcoding technology for multiplexing.
• Incorporated design innovations to enhance assay sensitivity and correct for plate-to-plate variations.

Main Results:

• Identified and validated a series of broad-acting inhibitors against coronavirus proteases.
• A medicinal chemistry campaign successfully improved the potency of a lead inhibitor while preserving its broad-spectrum activity.
• The multiplex screening approach significantly reduced the time and cost compared to traditional methods.

Conclusions:

• The established high-throughput multiplex screening platform efficiently explores vast chemical spaces for antiviral drug discovery.
• This platform accelerates the identification of novel therapeutic agents, enhancing preparedness against future viral threats.
• The uncovered broad-acting coronavirus protease inhibitors represent promising leads for developing new antiviral therapies.