Broad Tricyclic Ring Inhibitors Block SARS-CoV-2 Spike Function Required for Viral Entry

Area of Science:

• Virology
• Drug Discovery
• Structural Biology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via spike glycoprotein binding to the ACE2 receptor.
• This interaction triggers conformational changes essential for viral and cellular fusion.

Purpose of the Study:

• To identify selective and broad-spectrum inhibitors of SARS-CoV-2 entry.
• To elucidate the mechanism of inhibition and identify conserved targets on the viral spike protein.

Main Methods:

• Experimental identification of tricyclic ring-containing compounds as entry inhibitors.
• Analysis of inhibitor interaction with the SARS-CoV-2 spike receptor binding domain.
• Assessment of inhibitor effects on spike protein conformation, assembly, and cell-cell fusion.

Main Results:

• Selective and broad inhibitors of SARS-CoV-2 entry were identified.
• Inhibitors interacted with the spike protein's receptor binding domain, affecting early infection steps without blocking ACE2 binding.
• Compounds induced conformational changes, affected spike assembly, and inhibited spike-mediated cell-cell fusion.
• Broad inhibitors target a conserved pocket on SARS-CoV and SARS-CoV-2 spikes, blocking entry-mediating activity.

Conclusions:

• Identified inhibitors offer new insights into SARS-CoV-2 spike structure and viral entry mechanisms.
• These compounds represent promising lead candidates for developing broad-range entry inhibitors against SARS-CoVs.