High-throughput screening identifies broad-spectrum Coronavirus entry inhibitors

Area of Science:

• Virology
• Drug Discovery
• Molecular Biology

Background:

• The COVID-19 pandemic underscored the urgent need for effective antivirals against emerging coronaviruses (CoVs).
• Inhibiting the spike (S) glycoprotein-mediated viral entry presents a promising therapeutic strategy.
• Targeting viral entry downstream of receptor binding is crucial for developing broad-spectrum antivirals.

Purpose of the Study:

• To establish a high-throughput screening (HTS) platform for identifying small molecule inhibitors of coronavirus entry.
• To screen a large library of small molecules for compounds that inhibit SARS-CoV-2 S glycoprotein-mediated viral entry.
• To discover novel broad-spectrum antiviral agents effective against emerging coronaviruses.

Main Methods:

• Development of a pseudovirus-based high-throughput screening (HTS) platform.
• Screening of approximately 200,000 small molecules against SARS-CoV-2 S-bearing pseudoviruses.
• Counter-screening and validation against MERS-CoV, SARS-CoV-2 variants (Alpha, Delta, Omicron), and authentic SARS-CoV-2.

Main Results:

• Identified 65 SARS-CoV-2 S-specific inhibitors after counter-screening.
• Five compounds, including Nafamostat, showed activity against MERS-CoV S-bearing pseudoviruses.
• An unreported inhibitor and its derivative demonstrated potential as broad-spectrum antivirals against SARS-CoV-2 variants and authentic virus.

Conclusions:

• The developed HTS platform is effective for identifying coronavirus entry inhibitors.
• A novel inhibitor and its derivative show promise as broad-spectrum antivirals.
• Further validation is warranted to explore the therapeutic potential of these compounds against emerging CoVs.