{"title":"Natural 7,8-secolignans from Schisandra sphenanthera fruit potently inhibit SARS-CoV-2 3CLpro and inflammation","authors":"","doi":"10.1016/j.jtcme.2024.01.005","DOIUrl":null,"url":null,"abstract":"<div><p>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 (3CL<sup>pro</sup>) is a promising target for developing anti-coronavirus drugs. <em>Schisandra sphenanthera</em> 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 3CL<sup>pro</sup>. 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 <em>in vitro</em> experiments, we found that two epimeric 7,8-secolignans, rel-(1<em>S</em>,2<em>R</em>)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (<strong>2</strong>) and rel-(1<em>S</em>,2<em>S</em>)-1-(3,4-dimethoxyphenyl)-2-methyl-3-oxobutyl-3,4-dimethoxybenzoate (<strong>4)</strong>, potently inhibited 3CL<sup>pro</sup> with IC<sub>50</sub> values of 4.88 ± 0.60 μM and 4.75 ± 0.34 μM, respectively. Moreover, <em>in vivo</em> and <em>in vitro</em> experiments indicated that compounds <strong>2</strong> and <strong>4</strong> were potent in regulating the inflammatory response and preventing lung injury. Our findings indicate that compounds <strong>2</strong> and <strong>4</strong> may emerge as promising SARS-CoV-2 inhibitors via 3CL<sup>pro</sup> inhibition and anti-inflammatory mechanisms.</p></div>","PeriodicalId":17449,"journal":{"name":"Journal of Traditional and Complementary Medicine","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2225411024000051/pdfft?md5=914963c5062bc3674328c441064b5621&pid=1-s2.0-S2225411024000051-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Traditional and Complementary Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2225411024000051","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"INTEGRATIVE & COMPLEMENTARY MEDICINE","Score":null,"Total":0}
引用次数: 0
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.