Glycyrrhetinic Acid Prohibiting Fusion Peptides from Fusing with Cell Membrane

Abstract The inhibition of the fusion peptide (FP) of the spike protein of coronaviruses, which mediates interactions with the host cell membrane, plays a critical role in the membrane fusion process. In this study, we investigated the interactions between the FP and cell membranes and evaluated the effect of three drug molecules — neferine (Nef), glycyrrhetinic acid (GA), quercetin (Qct) on the membrane fusion process by combining molecular dynamics (MD) simulations and experimental methods. Our findings revealed that glycyrrhetinic acid exhibited strong binding ability towards the FP (residues 815–828), with particularly interactions observed with key residues L821, L822, F823, and L828. Furthermore, we performed FITC fluorescence staining experiments on cells and assessed the inhibitory effects of glycyrrhetinic acid on FP. The results showed a significant reduction in fluorescence intensity in the FP‐FITC experiment group treated with glycyrrhetinic acid, indicating that glycyrrhetinic acid interferes with the binding ability of FP and disrupts its localization on the cell membrane. Overall, this research will contribute to a deeper understanding of the inhibition mechanism of FP's membrane fusion process, which widely exists in the intrusion process between viruses and cells.