Schaftoside inhibits 3CLpro and PLpro of SARS-CoV-2 virus and regulates immune response and inflammation of host cells for the treatment of COVID-19

Yang, Yi; Zhang, Meng; Xue, Heng; Yu, Rong; Bao, Yang-Oujie; Kuang, Yi; Chai, Yue; Wen, Ming‐Shien; Wang, Jing; Shi, Xiaomeng; Li, Wenzhe; Hong, Wei; Li, Junhua; Muturi, Ephantus J.; Wei, Hongping; Włodarz, Joachim J.; Roszak, Szczepan; Qiao, Xue; Yang, Hang; Ye, Min

doi:10.1016/j.apsb.2022.07.017

Cited by 40 publications

(28 citation statements)

References 42 publications

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“…The inhibition activity against S‐RBD was measured by ELISA as described in our previous study (Yi et al ., 2022a,b). Briefly, the spike protein DRA49 (0.3 μg/mL) was incubated in the coating solution (Na 2 CO 3 1.59 mg/mL, NaHCO 3 2.93 mg/mL, pH 9.6) on 96‐well microplates at 4 °C overnight.…”

Section: Methodsmentioning

confidence: 99%

“…Tetramethyl benzidine was used as the chromogenic agent. Finally, the reaction was stopped by 1 M HCl and the enzyme activity was determined at OD 450nm on LabServ K3 Microplate Reader (Thermo Fisher Scientific, USA; Yi et al ., 2022a,b).…”

Section: Methodsmentioning

confidence: 99%

“…For 3CL pro , the reaction mixture contained 12.5 μg/mL protein, 3 mM substrate, 8 μM candidate compound or positive drug (GC376), in 20 mM Tris–HCl (pH 7.0) as the reaction buffer. After incubated at 25 °C for 10 min, the fluorescence was detected (emission at 490 nm and excitation at 340 nm) on a FlexStation 3 Multi‐Mode Microplate Reader (Molecular Devices, China; Dai et al ., 2020; Yi et al ., 2022a,b). For PL pro , the reaction mixture contained 12.5 μg/mL protein, 5 mM substrate, 8 μM candidate compound or positive drug (GRL0617), in 50 mM HEPES (pH 7.5) as the reaction buffer.…”

Section: Methodsmentioning

confidence: 99%

“…For PL pro , the reaction mixture contained 12.5 μg/mL protein, 5 mM substrate, 8 μM candidate compound or positive drug (GRL0617), in 50 mM HEPES (pH 7.5) as the reaction buffer. After incubated at 25 °C for 10 min, the fluorescence was detected (emission at 535 nm and excitation at 340 nm) on a FlexStation 3 Multi‐Mode Microplate Reader (Yi et al ., 2022a,b).…”

Section: Methodsmentioning

confidence: 99%

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Characterization and protein engineering of glycosyltransferases for the biosynthesis of diverse hepatoprotective cycloartane‐type saponins in Astragalus membranaceus

Chen

Zhang

Gao

et al. 2023

Plant Biotechnology Journal

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Although plant secondary metabolites are important source of new drugs, obtaining these compounds is challenging due to their high structural diversity and low abundance. The roots of Astragalus membranaceus are a popular herbal medicine worldwide. It contains a series of cycloartane-type saponins (astragalosides) as hepatoprotective and antivirus components. However, astragalosides exhibit complex sugar substitution patterns which hindered their purification and bioactivity investigation. In this work, glycosyltransferases (GT) from A. membranaceus were studied to synthesize structurally diverse astragalosides. Three new GTs, AmGT1/5 and AmGT9, were characterized as 3-O-glycosyltransferase and 25-Oglycosyltransferase of cycloastragenol respectively. AmGT1 G146V/I variants were obtained as specific 3-O-xylosyltransferases by sequence alignment, molecular modelling and site-directed mutagenesis. A combinatorial synthesis system was established using AmGT1/5/9, AmGT1 G146V/S and the reported AmGT8 and AmGT8 A394F . The system allowed the synthesis of 13 astragalosides in Astragalus root with conversion rates from 22.6% to 98.7%, covering most of the sugar-substitution patterns for astragalosides. In addition, AmGT1 exhibited remarkable sugar donor promiscuity to use 10 different donors, and was used to synthesize three novel astragalosides and ginsenosides. Glycosylation remarkably improved the hepatoprotective and SARS-CoV-2 inhibition activities for triterpenoids. This is one of the first attempts to produce a series of herbal constituents via combinatorial synthesis. The results provided new biocatalytic tools for saponin biosynthesis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Characterization and protein engineering of glycosyltransferases for the biosynthesis of diverse hepatoprotective cycloartane‐type saponins in Astragalus membranaceus

Chen

Zhang

Gao

et al. 2023

Plant Biotechnology Journal

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“…Moreover, five active components of licorice extract, Glycyrol, Isolicoflavonol, Licochalcone A, 18β-glycyrrhetinic acid, and Licoisoflavone A, can alleviate paraquat-induced ALI in mice by upregulating CYP 450 and Nrf 2 pathways [ 18 ]. Meanwhile, Schaftoside, the active ingredient of licorice, can treat COVID-19 by inhibiting 3CL pro and PL pro of SARS-CoV-2 virus and modulating immune response and inflammation of host cells [ 19 ]. Furthermore, Glycyrrhizin was shown to alleviate acute lung injury by inhibiting NLRP3 inflammasome [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Liquiritin exhibits anti-acute lung injury activities through suppressing the JNK/Nur77/c-Jun pathway

Zhou

Yang

et al. 2023

Chin Med

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Background Licorice (Glycyrrhiza uralensis Fisch.), a well-known traditional medicine, is traditionally used for the treatment of respiratory disorders, such as cough, sore throat, asthma and bronchitis. We aim to investigate the effects of liquiritin (LQ), the main bioactive compound in licorice against acute lung injury (ALI) and explore the potential mechanism. Methods Lipopolysaccharide (LPS) was used to induce inflammation in RAW264.7 cells and zebrafish. Intratracheal instillation of 3 mg/kg of LPS was used for induction an ALI mice model. The concentrations of IL-6 and TNF-α were tested using the enzyme linked immunosorbent assay. Western blot analysis was used to detect the expression of JNK/Nur77/c-Jun related proteins. Protein levels in bronchoalveolar lavage fluid (BALF) was measured by BCA protein assay. The effect of JNK on Nur77 transcriptional activity was determined by luciferase reporter assay, while electrophoretic mobility shift assay was used to examine the c-Jun DNA binding activity. Results LQ has significant anti-inflammatory effects in zebrafish and RAW264.7 cells. LQ inhibited the expression levels of p-JNK (Thr183/Tyr185), p-Nur77 (Ser351) and p-c-Jun (Ser63), while elevated the Nur77 expression level. Inhibition of JNK by a specific inhibitor or small interfering RNA enhanced the regulatory effect of LQ on Nur77/c-Jun, while JNK agonist abrogated LQ-mediated effects. Moreover, Nur77-luciferase reporter activity was suppressed after JNK overexpression. The effects of LQ on the expression level of c-Jun and the binding activity of c-Jun with DNA were attenuated after Nur77 siRNA treatment. LQ significantly ameliorated LPS-induced ALI with the reduction of lung water content and BALF protein content, the downregulation of TNF-α and IL-6 levels in lung BALF and the suppression of JNK/Nur77/c-Jun signaling, which can be reversed by a specific JNK agonist. Conclusion Our results indicated that LQ exerts significant protective effects against LPS-induced inflammation both in vivo and in vitro via suppressing the activation of JNK, and consequently inhibiting the Nur77/c-Jun signaling pathway. Our study suggests that LQ may be a potential therapeutic candidate for ALI and inflammatory disorders.

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Pharmacokinetic and oral bioavailability study of schaftoside in rats

Lin,

Wang,

et al. 2024

Biomedical Chromatography

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A simple and sensitive LC–tandem mass spectrometry method was established and validated for the determination of schaftoside in rat plasma. After prepared by protein precipitation with acetonitrile, schaftoside and internal standard were separated on a Waters HSS T3 column using acetonitrile containing 0.1% formic acid and 0.1% formic acid in water as the mobile phase by gradient elution. The method showed excellent linearity over the range of 0.5–500 ng/mL with acceptable intra‐ and inter‐day precision, accuracy, matrix effect, and recovery. The stability assay indicated that schaftoside was stable during the sample acquisition, preparation, and storage. The method was applied to a pharmacokinetic study of schaftoside in rats. The result suggested that after intravenous administration at a dose of 1 mg/kg, schaftoside was quickly eliminated from the plasma with an elimination half‐life of 0.58 h. After oral administration at doses of 5, 10, and 20 mg/kg, schaftoside was quickly absorbed into the plasma and reached the peak concentration (Cmax) of 45.1–104.99 ng/mL at 0.67–1.17 h. The increase of exposure (area under the curve) was linear with the increase of dose. The oral bioavailability was 0.42%–0.71% in the range of 5–20 mg/kg.

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Schaftoside inhibits 3CLpro and PLpro of SARS-CoV-2 virus and regulates immune response and inflammation of host cells for the treatment of COVID-19

Cited by 40 publications

References 42 publications

Characterization and protein engineering of glycosyltransferases for the biosynthesis of diverse hepatoprotective cycloartane‐type saponins in Astragalus membranaceus

Characterization and protein engineering of glycosyltransferases for the biosynthesis of diverse hepatoprotective cycloartane‐type saponins in Astragalus membranaceus

Liquiritin exhibits anti-acute lung injury activities through suppressing the JNK/Nur77/c-Jun pathway

Pharmacokinetic and oral bioavailability study of schaftoside in rats

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