EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2025
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IF 5.9
Yan-Yun Liu,Zheng-Ao Li,Yu-Zheng Zhou,Sen-Lin Wang,Zong-Peng Chen,Si-Xu Liu,Peng Zhan,Ying-Jun Zhou,Zan-Xian Xia,Xu Deng
The global COVID-19 pandemic caused by SARS-CoV-2 has underscored the urgent need for the development of new broad-spectrum antivirals to combat its high mutation rate and the emerging variants. Host ER α-glucosidases I/II are promising host-targeted therapeutic targets for the development of broad-spectrum antivirals against viral strains that depend on ERQC for infectivity. Herein, we designed and synthesized a series of TCM theory-inspired DNJ-flavonoid conjugates as novel α-glucosidase inhibitors, which were screened against their in vitro antiviral activities in non-replicative SARS-CoV-2 pseudovirus (PsV) assay. Remarkably, DNJ-20 not only demonstrated remarkable inhibition activity against α-glucosidase and viral entry process, but also exerted potent and broad-spectrum anti-coronaviral activity against SARS-CoV-2 pseudovirus (PsV), several SARS-CoV-2 variants, as well as HCoV-229E and HCoV-OC43, with EC 50 values up to 1.49 μM, which is more potent than the benchmark α-glucosidase inhibitor UV-4 ( DNJ-3 ). Besides, it had no observable cytotoxicity in HeLa-ACE2, HEK-293T and Beas-2B cells. Therefore, TCM theory-inspired DNJ-flavonoid conjugates can be served as promising drug leads for pan-coronavirus therapeutic development to combat current and future coronavirus pandemics.
研究领域:
药理学
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病毒学
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药物研发
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中医药学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2018
·Vol. 19
·期 6
·1699
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IF 3.687
Qing Zhao,Tian Zhu Jia,Qi Chen Cao,Fang Tian,Wan Tao Ying
The traditional Chinese drug Bombyx Batryticatus (BB), which is also named the white stiff silkworm, has been widely used in Chinese clinics for thousands of years. It is famous for its antispasmodic and blood circulation-promoting effects. Cardiomyocyte hypertrophy, interstitial cell hyperplasia, and myocardial fibrosis are closely related to theN-glycosylation of key proteins. To examine the alterations ofN-glycosylation that occur in diabetic myocardium during the early stage of the disease, and to clarify the therapeutic effect of 1-Deoxynojirimycin (1-DNJ) extracted from BB, we used the db/db (diabetic) mouse model and an approach based on hydrophilic chromatography solid-phase extraction integrated with an liquid Chromatograph Mass Spectrometer (LC-MS) identification strategy to perform a site-specificN-glycosylation analysis of left ventricular cardiomyocyte proteins. Advanced glycation end products (AGEs), hydroxyproline, connective tissue growth factor (CTGF), and other serum biochemical indicators were measured with enzyme-linked immunosorbent assays (ELISA). In addition, the α-1,6-fucosylation ofN-glycans was profiled with lens culinaris agglutinin (LCA) lectin blots and fluorescein isothiocyanate (FITC)-labelled lectin affinity histochemistry. The results indicated that 1-DNJ administration obviously downregulated myocardium proteinN-glycosylation in db/db mice. The expression levels of serum indicators and fibrosis-related cytokines were reduced significantly by 1-DNJ in a dose-dependent manner. The glycan α-1,6-fucosylation level of the db/db mouse myocardium was elevated, and the intervention effect of 1-DNJ administration onN-glycan α-1,6-fucosylation was significant. To verify this result, the well-known transforming growth factor-β (TGF-β)/Smad2/3 pathway was selected, and core α-1,6-fucosylated TGF-β receptor II (TGFR-βII) was analysed semi-quantitatively with western blotting. The result supported the conclusions obtained from LCA lectin affinity histochemistry and lectin blot analysis. The expression level of α-1,6-fucosyltransferase (FUT8) mRNA was also detected, and the results showed that 1-DNJ administration did not cause obvious inhibitory effects on FUT8 expression. Therefore, the mechanism of 1-DNJ for relieving diabetic cardiomyopathy (DCM)-associated fibrosis can be concluded as the inhibition ofN-acetylglucosamine (N-GlcNAc) formation and the reduction of substrate concentration.Keywords:1-DNJ;diabetic cardiomyopathy;fibrosis;N-glycosylation;α-1,6-fucosylation
研究领域:
药理学
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心脏病学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yangzhen Liao,Min Wu,Jiahe Fan,Jingqiong Wan,Xin An,Xiaolan Li,Yuan Wei,Zhen Ouyang
1-Deoxynojirimycin (DNJ), a primary active component in mulberry leaves, has garnered significant attention due to its unique structure and notable pharmacological properties. Our previous investigations have elucidated the biosynthetic pathways of DNJ from lysine to 2-methylpiperidine. However, the hydroxylation process and its underlying mechanisms remain elusive. In this study, five CYP450s hydroxylase genes significantly correlated ( P < 0.05) with DNJ content in mulberry leaves at various time were screened through transcriptome profile. MaCYP71BG22 was first cloned and functionally characterized. This gene was shown to specifically catalyze the stereoselective hydroxylation of ( R )-2-methylpiperidine at the C4-position to produce (2 R , 4 R )-2-methylpiperidin-4-ol. In hairy roots of mulberry, overexpression of MaCYP71BG22 increased DNJ accumulation, while virus-induced gene silencing (VIGS) decreased its production. Furthermore, structural-function analysis pinpointed a critical residue, G460, in MaCYP71BG22, mutation of this residue to G460E enhanced the enzyme's catalytic efficiency. This study represents the first report of a CYP450 hydroxylase involved in the biosynthesis of piperidine alkaloids in mulberry leaves, and demonstrates that MaCYP71BG22 selectively catalyzes the C4-stereoselective hydroxylation of ( R )-2-methylpiperidine in DNJ biosynthesis. These findings further elucidate the DNJ biosynthetic pathway and provide new insights into the stereo- and regio-selective hydroxylation abilities of CYP450s hydroxylase in DNJ biosynthesis.
研究领域:
植物生物化学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2022
·
IF 5.895
Fanshan Feng,Wei Xiang,Han Gao,Yanan Jia,Yuansong Zhang,Lingshu Zeng,Jiaxin Chen,Xianzhi Huang,Li Xu
Mulberry twigs are an important source of α-glucosidase inhibitors. To date, research studies on α-glucosidase in mulberry twigs have mainly focused on alkaloids such as 1-deoxynojirimycin (DNJ). Preliminary studies have shown that there may be more active nonalkaloid α-glucosidase inhibitors in mulberry twigs. In this study, we immobilized α-glucosidase on Fe3O4@SiO2 for the first time and rapidly screened four nonalkaloid α-glucosidase inhibitors (kuwanon G, kuwanon C, kuwanon H, and morusin) using ligand fishing technology with ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) from the mulberry twig extract of Jialing 20, the excellent artificial triploid variety of mulberry cultivated extensively in Southwest China. The half maximal inhibitory concentrations (IC50) of kuwanon H and kuwanon G were 2.82 ± 0.68 and 2.83 ± 0.31 μM, respectively, with better inhibition activity than that of DNJ (with an IC50 of 7.04 ± 0.82 μM). Meanwhile, the molecular docking results showed that the action sites of these two isopentenyl flavonoids on α-glucosidase were different from that of DNJ. In brief, this work is beneficial to discovering new α-glucosidase inhibitors from mulberry twigs quickly and accurately and provides a theoretical basis for the mulberry twig extract as a functional food or a natural hypoglycemic drug source, as well as a reference for directional breeding of mulberry, which greatly improves the exploitation and utilization value of mulberry twigs as an agricultural byproduct in the fields of agricultural production, functional food, and natural medicine.
研究领域:
药理学
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分析化学
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天然产物
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农业科学
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功能食品
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 13
·期 16
·8593-8604
·
IF 6.317
Yanfang Yu,Yuhuan Chen,Xuping Shi,Chuan Ye,Junwen Wang,Jinzhi Huang,Bing Zhang,Zeyuan Deng
This study investigated the hepatoprotective effects of various mulberry (Morus alba L.) leaf extracts (MLEs), including mulberry ethanol extract (MEE), aqueous extract (MAE) and a combination extract (MCE) against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury in rats. It aimed to explore the possible molecular mechanism of the liver-protecting function of mulberry leaves and provide a reference for choosing the appropriate extraction method. The results showed that the three extracts contained different amounts of phenolic compounds, 1-deoxynojirimycin (DNJ) and polysaccharides. MLEs markedly improved the pathological status of rat liver tissue, decreased the levels of AST, ALT, TNF-α, IL-1β, IL-6 and MDA, while increased the levels of GSH, SOD and CAT in the D-GalN/LPS-treated rats at the same time. MEE, with the highest amount of total phenolics, exhibited the highest antioxidant activity corresponding to the protein expression level of Nrf2 and HO-1. MCE significantly suppressed the expression of apoptosis-related dot-like protein (ASC) and Caspase-1 and inhibited the phosphorylation of p38 MAPK and ERK1/2, thereby showing high anti-inflammatory activity. These results indicated that the active components from mulberry leaves protected rats against acute liver injury, attributed to a reduction in both oxidative stress and inflammatory response. The protective effect may be implicated in regulating the Nrf2, NLRP3 and MAPK signaling pathways.
研究领域:
药理学
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肝病学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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