Effects of diarylbutane lignans from Schisandra chinensis fruit on SARS-CoV-2 3CL(pro) and PL(pro) and their in vitro anti-inflammatory properties.

BACKGROUND: Schisandra chinensis fruit is a well-known traditional Chinese medicine (TCM), whose extract has a potent inhibitory effect on the severe acute respiratory syndrome-coronavirus-2 (SARS‑CoV‑2) 3-chymotrypsin-like protease (3CL(pro)) and papain-like protease (PL(pro)). PURPOSE: This work aims to find the active components from the fruit of S. chinensis against SARS‑CoV‑2 3CL(pro) and PL(pro). MATERIALS AND METHODS: The chemical constituents of the fruit of S. chinensis were retrieved based on the electronic databases, such as Web of Science, PubMed, Medline Plus, and CNKI. Molecular docking was used to screen the active components against SARS‑CoV‑2 3CL(pro) and PL(pro). Potential hit compounds were further evaluated by enzymatic activity assay. Furthermore, the anti-inflammatory activities of the active compounds were further explored using the phorbol-12-myristate-13-acetate (PMA)-induced THP1 cells model. RESULTS: In this work, we retrieved 75 components of S. chinensis fruit, including 62 dibenzocyclooctadiene-type lignans, 3 diarylbutane-type lignans, 2 tetrahydrofuran-type lignans, and 8 nortriterpenoids. Combining molecular docking study and in vitro experiments, we found that pregomisin (63), meso‑dihydroguaiaretic acid (64), and nordihydroguaiaretic acid (65) could potently inhibit 3CL(pro) with IC(50) values of 3.07 ± 0.38, 4.12 ± 0.38, and 6.06 ± 0.62 μM, respectively, and inhibit PL(pro) with IC(50) values of 5.23 ± 0.33, 4.24 ± 0.46, and 16.28 ± 0.54 μM, respectively. Interestingly, compounds 63, 64, and 65 also have potent activities of regulating the inflammatory response in vitro. CONCLUSION: Our results suggest that compounds 63, 64, and 65 may be promising SARS-CoV-2 3CL(pro) and PL(pro) inhibitors and anti-inflammatory.