Therapeutic strategies for the fatty-acid-binding pocket of the spike protein: advances and perspectives.

The trimeric spike protein plays a crucial part in the lifecycle of SARS-CoV-2 by facilitating viral entry. The SARS-CoV-2 spike protein harbors a fatty-acid-binding pocket (FABP) at the interface between two adjacent receptor-binding domains. Ligand engagement at the FABP locks the spike into a non-infectious, closed conformation, thereby impairing the virus's ability to infect new cells. Herein, we summarize the small-molecule inhibitors targeting the FABP that have been described to date, analyzing their binding modes, SAR and mechanisms of action. Because this pocket is conserved across highly pathogenic coronaviruses, targeting it offers a promising strategy for developing novel antivirals with broad-spectrum anti-coronavirus activity. We hope this review will stimulate further research on FABP inhibitors and promote the discovery of broad-spectrum anti-SARS-CoV-2 therapeutics.