Sulfated polysaccharides from Laminaria japonica and Porphyra inhibit SARS-CoV-2 main protease: mechanistic insights into molecular interactions.

The replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in host cells relies on its non-structural protein, the main protease (Mpro), a cysteine protease that serves as a primary target for antiviral drug design. Here, the inhibitory effects of sulfated polysaccharides from Laminaria japonica (IJSPS) and Porphyra (PSPS) on Mpro activity were investigated. IJSPS displayed a marked inhibitory effect on Mpro activity, whereas PSPS showed no effect. The half maximal inhibitory concentration (IC50) and inhibition constant (Ki) of the IJSPS for Mpro activity are 1.17 ± 0.34 nM and 1.05 nM, respectively, which is significantly stronger than that of chondroitin sulfate and heparin. Fluorescence quenching experiments indicated that both sulfated polysaccharides interact with Mpro via hydrogen bonds and van der Waals forces. At 25 °C and 0.15 M salt concentration, the dissociation constants (KD) for the interactions of IJSPS and PSPS with Mpro are 7.82 and 8.33 μM, respectively. Furthermore, molecular docking and molecular dynamics (MD) simulations suggested that IJSPS may bind to the active site region of Mpro and form a stable complex with it, providing supportive theoretical evidence for the experimental findings. Our findings indicate that sulfated polysaccharides from Laminaria japonica exhibit strong inhibitory activity against SARS-CoV-2 Mpro, highlighting their potential as functional food components that may contribute to antiviral defense and support host health.