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. 2024 Jan 16;14(5):501-509.
doi: 10.1016/j.jtcme.2024.01.005. eCollection 2024 Sep.

Natural 7,8-secolignans from Schisandra sphenanthera fruit potently inhibit SARS-CoV-2 3CLpro and inflammation

Bin Li  1 , Liansheng Qiao  2 , Jianuo Zhang  1 , Qi Xiao  1 , Jiushi Liu  1 , Bengang Zhang  1 , Haitao Liu  1
Affiliations

Natural 7,8-secolignans from Schisandra sphenanthera fruit potently inhibit SARS-CoV-2 3CLpro and inflammation

Bin Li et al. J Tradit Complement Med. .

Abstract

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), turned into a global pandemic, and there remains an urgent demand for specific/targeted drugs for the disease. The 3C-like protease (3CLpro) is a promising target for developing anti-coronavirus drugs. Schisandra sphenanthera fruit is a well-known traditional Chinese medicine (TCM) with good antiviral activity. This study found that the ethanolic extract displayed a significant inhibitory effect against SARS-CoV-2 3CLpro. Forty-four compounds were identified in this extract using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Combining molecular docking and in vitro experiments, we found that two epimeric 7,8-secolignans, rel-(1S,2R)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (2) and rel-(1S,2S)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (4), potently inhibited 3CLpro with IC50 values of 4.88 ± 0.60 μM and 4.75 ± 0.34 μM, respectively. Moreover, in vivo and in vitro experiments indicated that compounds 2 and 4 were potent in regulating the inflammatory response and preventing lung injury. Our findings indicate that compounds 2 and 4 may emerge as promising SARS-CoV-2 inhibitors via 3CLpro inhibition and anti-inflammatory mechanisms.

Keywords: 3C-like protease; 7,8-Secolignans; COVID-19; Inflammation; SARS-CoV-2; Schisandra sphenanthera fruit; UPLC-Q/TOF-MS.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Inhibition of S. sphenanthera fruits extract (SSE) against SARS-CoV-2 3CLproin vitro.
Fig. 2
Fig. 2
The total ion chromatogram (TIC) of the ethanol extract of S. sphenanthera fruits (A), and the MS spectra as well as possible fragmentation pathways of compound 2/4 (B) in positive ion mode.
Fig. 3
Fig. 3
Binding modes of compounds 2 and 4 with 3CLpro by CDOCKER analysis. (A) The crystal structure of 3CLpro (6M2N) and the binding mode of the initial ligand (baicalein). (B) Binding mode of compound 2 with 3CLpro. (C) Binding mode of compound 4 with 3CLpro.
Fig. 4
Fig. 4
The inhibitory activities of compounds 2 (A) and 4 (B) against SARS-CoV-2 3CLpro.
Fig. 5
Fig. 5
Effect of compounds 2 and 4 on the histopathological changes in lung tissues in normal and LPS-induced ALI mice. (A) The images of representative haematoxylin and eosin (H&E)-stained lung sections. (B) Pathology evaluation for the therapeutic effect of compounds 2 and 4. ###P < 0.01 vs. control group, *P < 0.05, **P < 0.01, ***P < 0.001 vs. model group.
Fig. 6
Fig. 6
Effect of compounds 2 and 4 on IL-6 (A), TNF-α (B), IL-8 (C), and IL-1β (D) production in BALF. The data are the mean ± SD (n = 5). ###P < 0.01 vs. control group, *P < 0.05, **P < 0.01, ***P < 0.01 vs. model group.
Fig. 7
Fig. 7
Effect of compounds 2 and 4 on NO production in LPS-induced RAW 264.7 cells. (A) Cytotoxic activity of compounds 2 and 4 against RAW 264.7 cells at a concentration of 50 μM. (B) Level of NO treated with compounds 2 and 4 (12.5, 25, and 50 μM) in LPS-induced RAW 264.7 cells. The data are the mean ± SD (n = 3). ##P < 0.01 vs. control group, *P < 0.05, **P < 0.01 vs. model group.
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