Communications Chemistry
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2025
·Vol. 8
·期 1
·1-12
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IF 6.2
Bai Si-Cong,Wang Ye-Cheng,Ye Wei-Lin,Wu Sheng-Yen,Jia Lee,Hong Liu,Xie Huan-Zhang,Li Gao
Abnormal amyloid beta (Aβ) aggregation is a key factor in Alzheimer’s disease (AD) pathology. Despite efforts to develop Aβ aggregation inhibitors, efficient screening strategies remain limited. Here, we initially applied structure-based virtual screening to target Aβ fibril ends, aiming to identify compounds that could effectively combat AD neurodegeneration. Using this approach, we screened a traditional Chinese medicine library with thousands of compounds, and selected high-scoring hits likely to inhibit fibril elongation or promote fibril depolymerization. Forsythoside A emerged as the most potent inhibitor, effectively reducing Aβ 40 aggregation and disassembling pre-formed fibrils, as confirmed through biophysical assays and surface plasmon resonance analysis. Chemical kinetics further elucidated its inhibitory mechanism. In Caenorhabditis elegans , forsythoside A alleviated Aβ-induced toxicity and extended the lifespan of the AD transgenic models. Further virtual screening and experimental validation using a CNS-penetrant compound library confirmed the robustness of our strategy. Our study underscores the effectiveness of virtual screening in the identification of Aβ aggregation inhibitors and emphasizes the critical significance of targeting fibril ends.
研究领域:
结构生物学
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药物筛选
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神经科学
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生物物理学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2025
·
IF 3.1
Liqing Wang,Menghan Chen,Hanxue Wang,Qihui Sun,Sujuan Zheng,Xiaoyun Liu,Yong Yang,Rong Rong
Clinical studies have demonstrated that many traditional Chinese medicines (TCM) exhibit not only antiviral effects but also efficacy in alleviating clinical symptoms of Coronavirus Disease 2019 (COVID-19). However, the pharmacologically active constituents responsible for their anti-COVID-19 efficacy remain unclear. This study aimed to establish a novel strategy for identifying active ingredients from herbs clinically used for COVID-19. An integrated approach combining data mining with Affinity Ultrafiltration (AUF) was developed. Initially, using a data mining strategy, high-frequency herbs were selected from the herbs clinically used in COVID-19. Furthermore, AUF technology was used to screen for potential bioactive components from the high-frequency herbs. The anti-COVID-19 potential of active compounds was assessed through enzyme activity assays and molecular docking, followed by validation in cellular and animal models. Data mining revealed that Glycyrrhiza uralensis Fisch., Lonicera japonica Thunb. and Forsythia suspensa (Thunb.) Vahl were the high-frequency herbs used in COVID-19. Five potential 3-Chymotrypsin-like protease (3CL pro ) inhibitors were screened from three herbs via AUF and identified using high-resolution mass spectrometry. Further enzymatic and cellular assays demonstrated that Licochalcone C (LCC) and Forsythiaside A (FTA) inhibited Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) replication at micromolar concentrations. Notably, FTA treatment significantly suppressed the elevation of pulmonary parameters and inflammatory mediators induced by SARS-CoV-2 nucleocapsid protein in mice. In summary, this study proposes a novel strategy integrating data mining with AUF to discover active compounds from TCM. Two components, LCC and FTA, were identified as dose-dependent inhibitors of SARS-CoV-2 Omicron strain replication in vitro.
研究领域:
药理学
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病毒学
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药物化学
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生物信息学
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植物学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2025
·Vol. 30
·期 5
·1187
·
IF 4.6
Sisi Pu,Yangyang Pan,Zuoyang Wang,Huimin Liu,Jianhui Zhang,Qian Zhang,Meng Wang
Overdose intake of acetaminophen (APAP) causes liver injury involving hepatic drug metabolism and activation of oxidative stress pathways, and forsythiaside A (FA) has hepatoprotective pharmacological activity, but knowledge of the mechanism of FA treatment for APAP liver injury is still lacking the literature. In this study, we investigated the effects of FA on the pregnane X receptor (PXR) by molecular docking and reporter gene assays. In addition, we explored the effects of FA on oxidative stress, endoplasmic reticulum stress (ERS), apoptosis, and hepatic pathology by interfering withPXRin ex vivo and in vivo models. The results showed that FA decreased thePXRprotein expression level and effectively reduced the oxidative stress level in the APAP model. In addition, FA reduced the expression of ERS pathway ProteinkinaseR-likeERkinase (PERK)-translation initiation factor 2 (eIF-2α)-activating transcription factor 4 (ATF4) by inhibitingPXR, and at the same time, decreased the expression of apoptotic proteins C/EBP homologous protein (CHOP), Bax, Caspase 3, and Caspase 7, and elevated the expression of apoptosis-suppressing protein Bcl-2, which ultimately treated the hepatic pathology injury of APAP in mice. The present study confirmed that FA improved APAP metabolism by inhibitingPXR-mediated CYP1A2 and CYP3A11 and alleviated APAP-induced hepatic impairment by inhibiting hepatic oxidative stress, ERS, and apoptosis.
研究领域:
药理学
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毒理学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
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