Psoralen and seselin stabilize the α-helix structure in lysozyme and inhibit the α-helix to β-sheet exchange: an efficient anti-amyloidogenic mechanism

Purpose: More than thirty human proteins have natural propensity to misfold and amyloid fibril formation that are important in the initiation and development of neurodegenerative disease. Therefore, preventing or reversing amyloid aggregation by using drugs or plant-based small molecules such as coumarin compounds could be useful. This study aimed to investigate the anti-amyloidogenic potential of psoralen and seselin, two types of coumarin compounds, on hen egg white lysozyme (HEWL) as a model system. Method: ThioflavinT (ThT), Congo red and ANS fluorescence, electron microscopy and circular dichroism were used to fibrillogenesis assay and structural analysis in the presence and absence of the compounds. Interaction of HEWL and coumarins evaluated by using surface plasmon resonance (SPR) and molecular docking and simulation. Results: The results indicated the ThT and ANS fluorescence intensities decreased in the presence of psoralen and seselin in a dose-dependent dependent manner, suggesting a strong inhibitory effect of compounds on HEWL fibril formation. The results confirmed coumarins could destabilize the pre-formed fibrils. Furthermore, Fluorescence analysis confirmed that coumarin interaction induces conformational changes in HEWL, evidenced by formation of non-fluorescent complexes and altered microenvironments around Tyr and Trp residues. CD spectrum revealed that coumarins can inhibit the α-helix to β-sheet exchange. SPR results showed psoralen could bind to HEWL more tightly. Conclusion: In agreement with experimental results, the molecular docking studies confirmed the conformational changes of HEWL upon interaction with psoralen and seselin. This study adds to the body of knowledge about rational drug design against the amyloidogenesis process.