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Activation of NF-κB Signaling by Optogenetic Clustering of IKKα and β. IKKα和β光遗传聚类激活NF-κB信号。
IF 2.6 3区 生物学
Advanced biology Pub Date : 2025-07-29 DOI: 10.1002/adbi.202400384
Alexandra Anna Maria Fischer, Markus Michael Kramer, Miguel Baños, Merlin Moritz Grimm, Manfred Fliegauf, Bodo Grimbacher, Gerald Radziwill, Sven Rahmann, Wilfried Weber
{"title":"Activation of NF-κB Signaling by Optogenetic Clustering of IKKα and β.","authors":"Alexandra Anna Maria Fischer, Markus Michael Kramer, Miguel Baños, Merlin Moritz Grimm, Manfred Fliegauf, Bodo Grimbacher, Gerald Radziwill, Sven Rahmann, Wilfried Weber","doi":"10.1002/adbi.202400384","DOIUrl":"https://doi.org/10.1002/adbi.202400384","url":null,"abstract":"<p><p>Molecular optogenetics allows the control of molecular signaling pathways in response to light. This enables the analysis of the kinetics of signal activation and propagation in a spatially and temporally resolved manner. A key strategy for such control is the light-inducible clustering of signaling molecules, which leads to their activation and subsequent downstream signaling. In this work, an optogenetic approach is developed for inducing graded clustering of different proteins that are fused to eGFP, a widely used protein tag. To this aim, an eGFP-specific nanobody is fused to Cryptochrome 2 variants engineered for different orders of cluster formation. This is exemplified by clustering eGFP-IKKα and eGFP-IKKβ, thereby achieving potent and reversible activation of NF-κB signaling. It is demonstrated that this approach can activate downstream signaling via the endogenous NF-κB pathway and is thereby capable of activating both an NF-κB-responsive reporter construct as well as endogenous NF-κB-responsive target genes as analyzed by RNA sequencing. The generic design of this system is likely transferable to other signaling pathways to analyze the kinetics of signal activation and propagation.</p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":" ","pages":"e00384"},"PeriodicalIF":2.6,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Fibronectin Peptide Modified Hydrogels Activate a Contractile Phenotype in Nucleus Pulposus Cells. 纤维连接蛋白肽修饰的水凝胶激活髓核细胞的收缩表型。
IF 2.6 3区 生物学
Advanced biology Pub Date : 2025-07-27 DOI: 10.1002/adbi.202500315
Ananya Naha, John Sorensen, Santiago Lazarte, Sailesti Joshi, Tristan P Driscoll
{"title":"Fibronectin Peptide Modified Hydrogels Activate a Contractile Phenotype in Nucleus Pulposus Cells.","authors":"Ananya Naha, John Sorensen, Santiago Lazarte, Sailesti Joshi, Tristan P Driscoll","doi":"10.1002/adbi.202500315","DOIUrl":"https://doi.org/10.1002/adbi.202500315","url":null,"abstract":"<p><p>Degenerative disc disease is strongly associated with low back pain, making it a leading cause of disability. With injury and age, cellular remodeling of the disc tissue leads to compositional changes, stiffening, and loss of stress relaxation, particularly in the central gelatinous nucleus pulposus (NP) region of the disc. As part of this extracellular matrix (ECM) remodeling, there is an increase in the deposition of fibronectin, a strongly adhesive integrin ligand that is known to regulate inflammatory signaling. However, it is unclear how these pathological changes in cellular adhesion regulate cell phenotype, and which domains of fibronectin are specifically involved. Here, a dextran vinyl sulfone (DexVS) hydrogel system is employed for presentation of specific fibronectin domains. Fibronectin peptides are found to enhance YAP signaling, inflammatory NF-κB signaling, cellular adhesion, and cellular contractility in NP cells, which leads to a decrease in aggrecan gene expression. Covalent modification of these DexVS hydrogels with bioactive peptides allows for targeted interactions with specific integrin receptors that are involved in healthy or degenerative signaling. In doing so, the integrin binding peptides from fibronectin are identified to activate a contractile phenotype in NP cells.</p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":" ","pages":"e00315"},"PeriodicalIF":2.6,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tumor Immune Engineering: Developing In Vitro Assays to Understand the Tumor-Immune Crosstalk. 肿瘤免疫工程:开发了解肿瘤免疫串扰的体外试验。
IF 3.2 3区 生物学
Advanced biology Pub Date : 2025-07-21 DOI: 10.1002/adbi.202400735
Ranjani N Iyer, Maitreyee Vartak, Tuli Dey
{"title":"Tumor Immune Engineering: Developing In Vitro Assays to Understand the Tumor-Immune Crosstalk.","authors":"Ranjani N Iyer, Maitreyee Vartak, Tuli Dey","doi":"10.1002/adbi.202400735","DOIUrl":"https://doi.org/10.1002/adbi.202400735","url":null,"abstract":"<p><p>Interaction between a growing tumor and the host immune system has various facets, which eventually influence the fate of both the tumor and the host. In the last decade, multiple efforts have been undertaken to mimic the heterogeneous consortium of tumors to comprehend tumor biology. Understanding the tumor-stromal or tumor-immune crosstalk is also crucial for screening and pre-clinical evaluation of therapeutic candidates. The development of human-relevant and physiologically similar models is the need of the hour to bridge the gap. Existing models relevant to tissue engineering, including porous scaffolds, hydrogel, and fibrous mats, are widely utilized to recapitulate the tumor microenvironment. In spite of their inherent limitations, they are employed to study tumor-immune interactions in the past. In the recent decade, emerging techniques such as Microfluidics, organ on a chip, and 3D Bioprinting have been used prevalently to mimic the heterogeneous landscape of tumors. This review is intended to discuss the current developments in the field of in vitro 3D tumor models while focusing on the tumor-immune crosstalk. Furthermore, the theoretical and practical limitations of the conventional model mimicking the tumorimmune crosstalk and the need for 'out of the box' ideas by converging the existing models are highlighted.</p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":" ","pages":"e00735"},"PeriodicalIF":3.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bacterial Quorum Sensing: A Double-Edged Sword in Cancer Development. 细菌群体感应:癌症发展的双刃剑。
IF 3.2 3区 生物学
Advanced biology Pub Date : 2025-07-21 DOI: 10.1002/adbi.202500023
Mirsadeghi Isfahani Paniz, Rastegar Lari Tina, Darbeheshti Farzaneh, Bahreini Farbod, Rezaei Nima
{"title":"Bacterial Quorum Sensing: A Double-Edged Sword in Cancer Development.","authors":"Mirsadeghi Isfahani Paniz, Rastegar Lari Tina, Darbeheshti Farzaneh, Bahreini Farbod, Rezaei Nima","doi":"10.1002/adbi.202500023","DOIUrl":"https://doi.org/10.1002/adbi.202500023","url":null,"abstract":"<p><p>Cancer is one of the most pervasive and severe global diseases that cause millions of death annually. Numerous bacterial strains are found to play fundamental roles in tumor formation, growth, and metastasis. On the other hand, specific bacterial strains are discovered to induce beneficial changes to restrict tumoral growth and progression or alter the tumor microenvironment. Studies have also suggested bacteria are potential microorganisms that transfer synthetic genes or anti-tumor drugs. A particularly interesting area of study is bacterial communication, known as quorum sensing (QS), in which signal peptides adjust bacterial pathogenic traits such as virulence factor, drug resistance, and biofilm after a threshold volume of signals is reached. QS signals raised a propitious future perspective against diseases and cancer. Future comprehension of the QS system can lead to novel bacterial-based therapeutic procedures with the minimum healthy cell toxicity and higher target specificity rather than long-established methods. This review aims to highlight significant research and advancements in the field of QS to combat cancer and find more non-toxic and less-invasive treatments.</p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":" ","pages":"e00023"},"PeriodicalIF":3.2,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
LIN28B Promotes Cancer Cell Dissemination and Angiogenesis. LIN28B促进癌细胞扩散和血管生成。
IF 3.2 3区 生物学
Advanced biology Pub Date : 2025-07-18 DOI: 10.1002/adbi.202400730
Diana Corallo, Sara Menegazzo, Marcella Pantile, Silvia Bresolin, Carlo Zanon, Alessandro Davini, Massimiliano Mazzone, Alessandra Biffi, Sanja Aveic
{"title":"LIN28B Promotes Cancer Cell Dissemination and Angiogenesis.","authors":"Diana Corallo, Sara Menegazzo, Marcella Pantile, Silvia Bresolin, Carlo Zanon, Alessandro Davini, Massimiliano Mazzone, Alessandra Biffi, Sanja Aveic","doi":"10.1002/adbi.202400730","DOIUrl":"https://doi.org/10.1002/adbi.202400730","url":null,"abstract":"<p><p>Neuroblastoma represents a major challenge in pediatric oncology with over 50% of cases involving metastasis. High-risk patients face an unfavorable prognosis, with survival rates below 40%. LIN28B plays a pivotal role in neuroblastoma development, being overexpressed in a subset of high-risk patients with widespread metastases. Here, the effect of induced LIN28B (iLIN28B) expression on neuroblastoma cells is investigated with a focus on key aspects of the metastatic cascade including anchorage, migration, invasion, and angiogenesis. iLIN28B cells show substrate-selective adherence, coating-dependent migration, and the context-guided ability to degrade the extracellular matrix. In response to tumor cell-derived IGF2, endothelial cells show enhanced motility and proliferation, while inhibition of IGF2 activity impairs LIN28B-induced angiogenesis in vitro and in vivo. These findings underscore the hub role of LIN28B in favoring pre-metastatic processes in neuroblastoma. The intricate interplay between LIN28B, endothelial cells, and the extracellular matrix contributes to the development of the aggressive neuroblastoma phenotypes.</p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":" ","pages":"e00730"},"PeriodicalIF":3.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Luteolin Regulates Mitophagy to Alleviate Myocardial Ischemia-Reperfusion Injury via Sirt3/Foxo3a Pathway. 木犀草素通过Sirt3/Foxo3a通路调节线粒体自噬减轻心肌缺血再灌注损伤
IF 3.2 3区 生物学
Advanced biology Pub Date : 2025-07-18 DOI: 10.1002/adbi.202400778
Li Yan, Lei Liang, Qiling Gou, Haoyu Wu, Mengya Dong, Hao Chen, Jiayu Diao
{"title":"Luteolin Regulates Mitophagy to Alleviate Myocardial Ischemia-Reperfusion Injury via Sirt3/Foxo3a Pathway.","authors":"Li Yan, Lei Liang, Qiling Gou, Haoyu Wu, Mengya Dong, Hao Chen, Jiayu Diao","doi":"10.1002/adbi.202400778","DOIUrl":"https://doi.org/10.1002/adbi.202400778","url":null,"abstract":"<p><p>Luteolin (LUT) belongs to a kind of flavonoid, which has protective effects on myocardial ischemia/reperfusion (I/R) injury. Sirt3 is located in mitochondria and interacts with Foxo3a to protect mitochondrial function against stress. Mitophagy is an important form of mitochondrial quality control. However, whether LUT regulates mitophagy to alleviate myocardial I/R injury via the Sirt3/Foxo3a pathway is rarely reported. In this study, 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP) is used to inhibit the Sirt3/Foxo3a pathway. Male adult rats are divided into four groups: Sham group, I/R group, I/R+LUT group, and I/R+LUT+3-TYP group. The I/R rats model is established by ligating the left anterior descending coronary artery for 30 min, then releasing the ligature for 24 h. Indexes of left ventricular function, myocardial damage, oxidative stress, and mitophagy are detected. It is found that LUT treatment activated Sirt3/Foxo3a pathway, improves left ventricular function, decreases myocardial infarction size, inhibits myocardial apoptosis and oxidative stress, and initiates mitophagy in I/R rats. Moreover, these protective effects of LUT are weakened when Sirt3 is inhibited. Together, LUT regulates mitophagy to alleviate myocardial I/R injury via the Sirt3/Foxo3a pathway.</p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":" ","pages":"e00778"},"PeriodicalIF":3.2,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Label-Free Detection of Lipid Accumulation in Cells Using Magnetic Levitation (Adv. Biology 7/2025) 利用磁悬浮无标记检测细胞内脂质积累(ad . Biology 7/2025)
IF 3.2 3区 生物学
Advanced biology Pub Date : 2025-07-15 DOI: 10.1002/adbi.70026
Kazim Kerim Moncal, Laeya Abdoli Najmi, Rakhi Gupta, Malavika Ramarao, Joshua W. Knowles, Chong Y. Park, Naside Gozde Durmus
{"title":"Label-Free Detection of Lipid Accumulation in Cells Using Magnetic Levitation (Adv. Biology 7/2025)","authors":"Kazim Kerim Moncal,&nbsp;Laeya Abdoli Najmi,&nbsp;Rakhi Gupta,&nbsp;Malavika Ramarao,&nbsp;Joshua W. Knowles,&nbsp;Chong Y. Park,&nbsp;Naside Gozde Durmus","doi":"10.1002/adbi.70026","DOIUrl":"https://doi.org/10.1002/adbi.70026","url":null,"abstract":"<p><b>Label-Free Detection of Lipid Accumulation via Magnetic Levitation</b></p><p>Magnetic levitation can be used for label-free profiling and characterization of lipid accumulation within cells, by separating cells based on their biophysical profiles. As pre-adipocytes differentiate, lipid accumulation occurs, leading to lower cell density and higher levitation heights. Four distinct layers can be seen within the magnetic levitation device: lipid vesicles (at top), mature adipocytes, adipocytes, and pre-adipocytes. More details can be found in article number 2200142 by Naside Gozde Durmus and co-workers.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":"9 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/adbi.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Application of Immune Repertoire Analysis in Differentiating Thyroid Cancer and Large Benign Thyroid Nodules (Adv. Biology 7/2025) 免疫库分析在甲状腺癌与甲状腺大良性结节鉴别中的应用(ad . Biology 7/2025)
IF 3.2 3区 生物学
Advanced biology Pub Date : 2025-07-15 DOI: 10.1002/adbi.70027
Jun Zhu, Xu Zhang, Xiangqing Zhu, Ziran Gao, Zhong Ni, Tiancheng Zhang, Meijin Huang
{"title":"Application of Immune Repertoire Analysis in Differentiating Thyroid Cancer and Large Benign Thyroid Nodules (Adv. Biology 7/2025)","authors":"Jun Zhu,&nbsp;Xu Zhang,&nbsp;Xiangqing Zhu,&nbsp;Ziran Gao,&nbsp;Zhong Ni,&nbsp;Tiancheng Zhang,&nbsp;Meijin Huang","doi":"10.1002/adbi.70027","DOIUrl":"https://doi.org/10.1002/adbi.70027","url":null,"abstract":"<p><b>Application of Immune Repertoire Analysis</b></p><p>This study analyzes peripheral TCR/BCR profiles in early thyroid cancer (PTC), large benign nodules, and healthy controls. Enhanced antigen-driven clonal expansion and disease-specific “public” clonotypes with unique V-J rearrangements were identified, linked to thyroid hormones/autoantibodies. Findings provide insights into immunopathological mechanisms, highlighting adaptive immune dynamics in thyroid disorders. More details can be found in article number 2400760 by Zhong Ni, Tiancheng Zhang, Meijin Huang, and co-workers.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":"9 7","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/adbi.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of Glutamine Metabolism Attenuates Tumor Progression Through Remodeling of the Macrophage Immune Microenvironment. 抑制谷氨酰胺代谢通过重塑巨噬细胞免疫微环境减缓肿瘤进展。
IF 3.2 3区 生物学
Advanced biology Pub Date : 2025-07-13 DOI: 10.1002/adbi.202400738
Tianhe Li, Sepehr Akhtarkhavari, Sumeng Qi, Jiawei Fan, Tu-Yung Chang, Yao-An Shen, JinMing Yang, Barbara S Slusher, Ie-Ming Shih, Stephanie Gaillard, Tian-Li Wang
{"title":"Inhibition of Glutamine Metabolism Attenuates Tumor Progression Through Remodeling of the Macrophage Immune Microenvironment.","authors":"Tianhe Li, Sepehr Akhtarkhavari, Sumeng Qi, Jiawei Fan, Tu-Yung Chang, Yao-An Shen, JinMing Yang, Barbara S Slusher, Ie-Ming Shih, Stephanie Gaillard, Tian-Li Wang","doi":"10.1002/adbi.202400738","DOIUrl":"10.1002/adbi.202400738","url":null,"abstract":"<p><p>Targeting glutamine metabolism has emerged as a promising strategy in cancer therapy. To attain clinical utility, a number of challenges must be overcome, including in vivo anti-tumor activity, pharmacological toxicity, and clinical safety. Aside from glutamine-addicted tumor cells, immune cells may also need glutamine to sustain physiological activities; thus, the current work used two immunological-intact murine cancer models to assess the effects of glutamine antagonists on tumor cells and the immune milieu. To minimize potential off-target effects, we developed a glutamine antagonist prodrug, JHU083, which is bioactivated selectively in cancer tissues. In both murine tumor models, we observed a significant anti-tumor effect, resulting in reduced tumor burden and impeded tumor progression. Single-cell RNA sequencing of tumor tissues demonstrated that JHU083 significantly hampered the immunosuppressive M2-like macrophages but not the pro-inflammatory M1-like macrophages. Expression of Myc- and hypoxia-regulated genes were also inhibited by JHU083. Ex vivo bone marrow-derived macrophage cultures further confirmed that M2 macrophages were more sensitive to glutamine antagonist than M1 macrophages. Together, our findings indicate that JHU083 exerted its anti-tumor activity not only through direct targeting of glutamine-addicted cancer cells but also by shifting the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment.</p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":" ","pages":"e00738"},"PeriodicalIF":3.2,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Pan-Enterovirus Natural Product Inhibitor Targeting a Unique Allosteric Site on the Viral 3C Protease. 一种针对病毒3C蛋白酶独特变构位点的泛肠病毒天然产物抑制剂
IF 3.2 3区 生物学
Advanced biology Pub Date : 2025-07-10 DOI: 10.1002/adbi.202400845
Shangwu Sun, Qiang Wang, Mengyao Zhu, Xuan Zhang, Xianfang Zhang, Bei Yang
{"title":"A Pan-Enterovirus Natural Product Inhibitor Targeting a Unique Allosteric Site on the Viral 3C Protease.","authors":"Shangwu Sun, Qiang Wang, Mengyao Zhu, Xuan Zhang, Xianfang Zhang, Bei Yang","doi":"10.1002/adbi.202400845","DOIUrl":"https://doi.org/10.1002/adbi.202400845","url":null,"abstract":"<p><p>Infections caused by Enterovirus like rhinoviruses, coxsackieviruses, and polioviruses represent a significant public health concern, for which there are no antivirals available yet. The highly conserved viral 3C protease has been the primary target for antiviral development, but competitive inhibitors targeting its active site does not meet expectations in clinical studies. Previously, an unconventional allosteric site is identified on human rhinovirus 14 (HRV14) 3C, representing novel opportunities for pan-enterovirus antivirals development. Here, in silico screening of 143,621 natural products against this allosteric site is performed and 28 candidate molecules are identified, among which dihydromyricetin (DHM) and oridonin-A1 bind to HRV14 3C and allosterically inhibit its protease activity. Moreover, DHM shows minimal cytotoxicity and potent antiviral efficacy against HRV14 infections across different cell models, with selective indexes exceeding 700. Structural analysis and mutagenesis assays further pinpoint key 3C residues essential for DHM binding. Consistent with the high conservation of these residues across Enterovirus genus, DHM broadly binds and efficiently inhibits 3C proteases from not only rhinoviruses, but also coxsackieviruses, enteroviruses and polioviruses. These findings establish DHM as a unique, broad-spectrum allosteric inhibitor of Enterovirus 3C proteases and underscore its potential as a promising candidate for the development of pan-enterovirus antivirals.</p>","PeriodicalId":7234,"journal":{"name":"Advanced biology","volume":" ","pages":"e00845"},"PeriodicalIF":3.2,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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