Acta Pharmaceutica Sinica. B最新文献_第2页

Machine learning-driven discovery of aniline phenylacetate derivatives as LasR-targeted biofilm inhibitors against Pseudomonas aeruginosa infections 机器学习驱动下发现苯胺苯乙酸衍生物作为激光靶向的铜绿假单胞菌感染的生物膜抑制剂

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2026-04-02 DOI: 10.1016/j.apsb.2026.03.048

Yujing Huang, Haoming Chen, Jiamin Wu, Xiaojie Huang, Yingxin Zhang, Anmin Ren, Xiao Wu, Chengyin Huang, Wenguan Xie, Duntao Zu, Congzhen Shen, Feifei Xu, Yiqun Chang, Liang Yang, Haibo Zhou, Pinghua Sun, Jun Xu, Jun Liu, Shengrong Li, Junxia Zheng

{"title":"Machine learning-driven discovery of aniline phenylacetate derivatives as LasR-targeted biofilm inhibitors against Pseudomonas aeruginosa infections","authors":"Yujing Huang, Haoming Chen, Jiamin Wu, Xiaojie Huang, Yingxin Zhang, Anmin Ren, Xiao Wu, Chengyin Huang, Wenguan Xie, Duntao Zu, Congzhen Shen, Feifei Xu, Yiqun Chang, Liang Yang, Haibo Zhou, Pinghua Sun, Jun Xu, Jun Liu, Shengrong Li, Junxia Zheng","doi":"10.1016/j.apsb.2026.03.048","DOIUrl":"10.1016/j.apsb.2026.03.048","url":null,"abstract":"<div><div><em>Pseudomonas aeruginosa</em> biofilm infections pose a severe clinical challenge due to antibiotic resistance driven by quorum sensing (QS). As the master regulator of the <em>P. aeruginosa</em> QS hierarchy, LasR controls biofilm initiation and key virulence factors, establishing it as a high-value therapeutic target. Here, we developed a machine learning pipeline integrating graph neural networks, pharmacophore modeling, molecular docking and molecular dynamics, and determined that the aniline-phenylacetic acid derivative (compound <strong>2g</strong>) is an effective LasR inhibitor. <strong>2g</strong> demonstrated exceptional biofilm inhibition (IC<sub>50</sub> = 0.14 ± 0.08 μmol/L) without bactericidal activity (MIC >256 μmol/L). and bound LasR with high affinity (<em>K</em><sub>D</sub> = 38.97 μmol/L). Mechanistically, transcriptomics revealed selective suppression of LasR-regulated virulence pathways, reducing pyocyanin production and bacterial motility. Notably, <strong>2g</strong> synergized with antibiotics <em>in vivo</em>, reducing effective doses of ciprofloxacin and tobramycin by 1000-fold and 500-fold, respectively, while potently suppressing resistance evolution. Pharmacokinetic profiling further demonstrated favorable oral bioavailability (26.8%) and a wide safety margin. This work establishes <strong>2g</strong> as a machine learning-optimized LasR inhibitor with potent antibiofilm activity and synergistic antibiotic enhancement, offering a translatable strategy against multidrug-resistant <em>P. aeruginosa</em> infections.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6852-6874"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular mechanisms of YZG-331 ameliorated insomnia based on the gut microbiota–drug interaction 基于肠道微生物-药物相互作用的YZG-331改善失眠的分子机制

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2026-07-17 DOI: 10.1016/j.apsb.2026.07.023

Hengtong Zuo, Qinglan Guo, Bin Zhao, Jinyue Lu, Ru Feng, Jingyue Wang, Jianye Song, Jingyu Jin, Jiachun Hu, Yi Zhao, Hui Xu, Tiefeng Yuan, Wanxia Wang, Yongmei Tu, Lingyu Wei, Yifan Zhao, Xiang Hui, Zhihao Liu, Li Sheng, Yan Li, Yan Wang

{"title":"Molecular mechanisms of YZG-331 ameliorated insomnia based on the gut microbiota–drug interaction","authors":"Hengtong Zuo, Qinglan Guo, Bin Zhao, Jinyue Lu, Ru Feng, Jingyue Wang, Jianye Song, Jingyu Jin, Jiachun Hu, Yi Zhao, Hui Xu, Tiefeng Yuan, Wanxia Wang, Yongmei Tu, Lingyu Wei, Yifan Zhao, Xiang Hui, Zhihao Liu, Li Sheng, Yan Li, Yan Wang","doi":"10.1016/j.apsb.2026.07.023","DOIUrl":"10.1016/j.apsb.2026.07.023","url":null,"abstract":"<div><div>The gut microbiota plays a crucial role in the study of drug efficacy and metabolism. YZG-331 exhibits significant sedative and hypnotic effects. However, the oral bioavailability of YZG-331 in female mice remains low at 27.7%, and it exhibits instability in the gut microbiota, undergoing rapid metabolism, with the intestinal hydrolytic metabolite M2 identified as the characteristic metabolite. Both the underlying mechanisms of YZG-331 therapeutic effects on insomnia and its enzyme-mediated metabolic pathways involving the gut microbiota remain incompletely elucidated. In this study, we found that YZG-331 regulated the tryptophan metabolism and 5-HT production pathways by the gut microbiota. Specifically, YZG-331 increased the abundance of <em>Lactobacillus</em> and <em>Muribaculaceae</em> in the gut, with <em>Lactobacillus reuteri</em> playing a critical role in both the metabolic processes of YZG-331 and the biosynthesis of tryptophan-derived metabolites. YZG-331 enhanced the activation of the tetrahydrobiopterin (BH<sub>4</sub>) cofactor system, which subsequently promoted tryptophan hydroxylase (TPH) activity, thereby enhancing 5-HT production. Furthermore, YZG-331 and M2 increased intestinal butyric acid levels, thereby promoting sleep regulation and supporting the restoration of the intestinal barrier. Overall, our study provided the first evidence highlighting the crucial role of the gut microbiota in the therapeutic mechanism and metabolic processing of YZG-331 in the treatment of insomnia.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6705-6730"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic targeting of the PRMT6/FOXK1 axis restores lipid homeostasis and ameliorates hepatic steatosis and steatohepatitis in mice 靶向治疗PRMT6/FOXK1轴可恢复小鼠脂质稳态并改善肝脂肪变性和脂肪性肝炎

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2026-08-06 DOI: 10.1016/j.apsb.2026.08.003

Yang Sun, Tao Chen, Lei Zhang, Jinlin Duan, Junyan Xue, Wentao Huang, Jianzhong Di, Yonglong Zhang

{"title":"Therapeutic targeting of the PRMT6/FOXK1 axis restores lipid homeostasis and ameliorates hepatic steatosis and steatohepatitis in mice","authors":"Yang Sun, Tao Chen, Lei Zhang, Jinlin Duan, Junyan Xue, Wentao Huang, Jianzhong Di, Yonglong Zhang","doi":"10.1016/j.apsb.2026.08.003","DOIUrl":"10.1016/j.apsb.2026.08.003","url":null,"abstract":"<div><div>Nonalcoholic fatty liver disease (NAFLD) is emerging as the leading cause of chronic liver disease, posing a global public health challenge without available therapeutic approaches. Protein arginine methyltransferase 6 is a type I PRMT that asymmetrically dimethylates arginine residues of a variety of substrates implicated in many diseases. However, its role in NAFLD pathologies has not been clarified. In this study, we show that PRMT6 is upregulated in NAFLD and NASH of mice and human patients. <em>Prmt6-</em>deficient mice are protected from diet-induced hepatic steatosis, steatohepatitis, insulin resistance, and glucose tolerance. Mechanistically, PRMT6 interacts with and dimethylates Forkhead box K1 (FOXK1) at four conserved arginine residues (R161, R191, R259, and R486), maintaining its nuclear localization and transcriptional activity as a repressor/activator, inhibiting fatty acid oxidation and stimulating lipogenesis programs, respectively. PRMT6 competes with glycogen synthase kinase-3 (GSK3) for binding to FOXK1 and triggers FOXK1 methylation. This methylation prevents FOXK1 from GSK3-mediated phosphorylation, leading to its dissociation from 14-3-3, enhanced nuclear retention, and transcriptional activity. Conversely, the methylation-defective FOXK1 mutant (4RK) has the opposite effect and confers resistance to diet-induced hepatic steatosis in mice. Moreover, pharmacological inhibition of PRMT6 by EPZ020411 ameliorates NAFLD progression in mice. Thus, our study demonstrates the PRMT6–FOXK1 axis as a critical regulator of NAFLD and that targeting PRMT6 represents a novel therapeutic intervention for NAFLD.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6780-6798"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BD2-selective BRD4 inhibitor ZX29 mitigates myocardial ischemia–reperfusion injury via BRD4–YY1–NCOA4 axis disruption and ferroptosis inhibition bd2选择性BRD4抑制剂ZX29通过BRD4 - yy1 - ncoa4轴断裂和抑制铁上吊减轻心肌缺血-再灌注损伤

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2026-07-30 DOI: 10.1016/j.apsb.2026.07.043

Zeyu Li, Meixiu Xin, Zhongkai Wu, Jing Lu, Ou Hu, Yong Zou, Peiqing Liu

{"title":"BD2-selective BRD4 inhibitor ZX29 mitigates myocardial ischemia–reperfusion injury via BRD4–YY1–NCOA4 axis disruption and ferroptosis inhibition","authors":"Zeyu Li, Meixiu Xin, Zhongkai Wu, Jing Lu, Ou Hu, Yong Zou, Peiqing Liu","doi":"10.1016/j.apsb.2026.07.043","DOIUrl":"10.1016/j.apsb.2026.07.043","url":null,"abstract":"<div><div>Myocardial ischemia/reperfusion injury (MI/RI) remains a major barrier to ischemic heart disease treatment, as reperfusion therapies often exacerbate cardiac damage. Bromodomain-containing protein 4 (BRD4) is a key epigenetic target in cardiovascular diseases, but pan-BRD4 inhibitors cause severe off-target toxicity by disrupting basal bromodomain 1 (BD1) function, highlighting the need for BD2-selective agents. This study aimed to develop a BD2-selective BRD4 inhibitor and clarify its mechanism. ZX29 was developed <em>via</em> virtual screening of 100,000 compounds and structure-based optimization, exhibiting potent BRD4 binding with an IC<sub>50</sub> of 0.27 ± 0.03 μmol/L and <em>K</em><sub>d</sub> of 1.68 μmol/L, outperforming clinical agent RVX-208. ZX29 specifically binds BRD4 BD2 <em>via</em> H437/V439 residues. In murine MI/RI models, oral ZX29 significantly improved cardiac systolic and diastolic function, reduced myocardial infarct size, and mitigated lipid peroxidation. Mechanistically, ZX29 disrupted the BRD4–Yin Yang 1 (YY1) interaction and inhibited the nuclear receptor coactivator 4 (NCOA4)–ferritin heavy chain 1 (FTH1) degradation axis, suppressing lysosomal ferrous iron release and ferroptosis. Moreover, ZX29 preserved mitochondrial function by maintaining mitochondrial membrane potential and boosting ATP production. Ultimately, this study validates selective BRD4 BD2 inhibition as a safe and effective therapeutic strategy for MI/RI and establishes ZX29 as a viable clinical candidate.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6731-6755"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A mechanistic quantitative systems pharmacology framework enriched by multiscale data enables model-informed translational development of mesenchymal stem cell therapy in lupus nephritis 由多尺度数据丰富的机制定量系统药理学框架使模型知情的间充质干细胞治疗狼疮肾炎的转化发展

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2026-08-25 DOI: 10.1016/j.apsb.2026.08.018

Sujie Zhang, Qixiang Zhang, Dandan Wang, Zichun Li, Xia Xiao, Qi Rao, Siyuan Yang, Yuchen Qu, Yiyang Xu, Ning Wei, Jing Wang, Yuan Gao, Lingyun Sun, Guangji Wang, Fang Zhou, Chen Zhao

{"title":"A mechanistic quantitative systems pharmacology framework enriched by multiscale data enables model-informed translational development of mesenchymal stem cell therapy in lupus nephritis","authors":"Sujie Zhang, Qixiang Zhang, Dandan Wang, Zichun Li, Xia Xiao, Qi Rao, Siyuan Yang, Yuchen Qu, Yiyang Xu, Ning Wei, Jing Wang, Yuan Gao, Lingyun Sun, Guangji Wang, Fang Zhou, Chen Zhao","doi":"10.1016/j.apsb.2026.08.018","DOIUrl":"10.1016/j.apsb.2026.08.018","url":null,"abstract":"<div><div>Lupus nephritis (LN) is a complex autoimmune disease and mesenchymal stem cells (MSCs), given their unique immune-modulatory potential, have emerged as a promising route for treating LN. Understanding the multiscale dynamic LN–MSC interactions and selecting the optimal clinical design for MSCs is critical to enhance their therapeutic potential and achieve meaningful benefit-risk differentiation in patients. To guide MSC clinical development, we constructed the first mechanistic quantitative systems pharmacology model of LN pathophysiology that integrated multimodal preclinical–clinical data, with detailed illustration of standard-of-care immunosuppressant pharmacology and physiologically-based biodistribution and therapeutic mechanisms of MSCs. We created model-based virtual LN patients that well captured clinical interpatient heterogeneity and were validated by numerous sets of clinical efficacy readouts, including first-hand results from our investigator-initiated trial testing MSCs in LN patients. We used this computational framework and identified that a spaced two-infusion MSC dosing strategy would yield optimal clinical response in LN patients, which directly informed the phase 2 design of a novel MSC therapy. Modeling analyses further identified that CXCL10 in combination with proteinuria are potential predictive biomarkers that could boost clinical renal response to MSCs. These results demonstrated the exceptional importance of our QSP framework in driving MSC clinical development for LN patients.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6756-6779"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Modulating macrophage efferocytosis: Drug delivery strategies for enhancement, mimicry, and inhibition 调节巨噬细胞efferocytosis：增强、模仿和抑制的药物递送策略

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2026-08-03 DOI: 10.1016/j.apsb.2026.07.051

Zhihua Liu, Jiahui Wu, Jiayan Lyu, Zhou Zhou, Yuan Huang

{"title":"Modulating macrophage efferocytosis: Drug delivery strategies for enhancement, mimicry, and inhibition","authors":"Zhihua Liu, Jiahui Wu, Jiayan Lyu, Zhou Zhou, Yuan Huang","doi":"10.1016/j.apsb.2026.07.051","DOIUrl":"10.1016/j.apsb.2026.07.051","url":null,"abstract":"<div><div>Efferocytosis, the non-inflammatory clearance of apoptotic cells, is essential for tissue homeostasis and inflammation resolution. Efferocytosis has different effects in the context of different diseases, providing a compelling therapeutic target. Impaired efferocytosis is linked to the progression of cardiovascular, autoimmune, and neurological disorders, whereas in tumors, efferocytosis often facilitates immunosuppression and metastasis. This review comprehensively summarizes recent advances in drug delivery systems (DDSs) designed for the modulation of macrophage efferocytosis. We first introduce the mechanisms of efferocytosis and its pathophysiological roles across diseases. Next, we thoroughly review DDSs designed to enhance, mimic, or inhibit efferocytosis, with a particular focus on various targeting methods to achieve precise efferocytosis modulation. Finally, we discuss translational challenges and propose future perspectives for efferocytosis-targeting therapies. This work aims to provide a foundational reference for the rational design of efferocytosis-modulating delivery systems and to underscore their therapeutic potential in a range of diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6632-6663"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","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 computational methods in the drug discovery and development of Alzheimer's disease 计算方法在阿尔茨海默病药物发现和开发中的应用

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2025-07-30 DOI: 10.1016/j.apsb.2025.07.038

Qianqian Zhang, Xiaoqing Gong, Huanxiang Liu, Xiaojun Yao

{"title":"Application of computational methods in the drug discovery and development of Alzheimer's disease","authors":"Qianqian Zhang, Xiaoqing Gong, Huanxiang Liu, Xiaojun Yao","doi":"10.1016/j.apsb.2025.07.038","DOIUrl":"10.1016/j.apsb.2025.07.038","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a prevalent neurodegenerative disorder marked by the accumulation of amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive decline. As the most common dementia, AD affects over 50 million individuals worldwide, with 10 million new cases each year. Despite many significant progresses in AD research fields, there is still no effective treatment. Advances in molecular modelling and artificial intelligence (AI) algorithm have facilitated the application of computational methods in AD drug development, offering advantages in terms of efficiency, cost–effectiveness, and resource conservation. These strategies, including molecular docking, molecular dynamics simulation, protein structure prediction, virtual screening, and <em>de novo</em> drug design, have been widely employed in the past decades. Additionally, AI pharmaceutical companies have revolutionized the traditional drug development pipeline such as AD biomarker discovery, accurate diagnosis and precision medicine, etc. This review offers a thorough summary of recent progresses in computational-based methodologies in the study of AD drug development, including the elucidation the pathological mechanism at the molecular level, target identification, target 3D structure prediction, lead compound discovery, <em>de novo</em> molecular generation, multi-target directed ligands, drug repurposing, biomarker discovery, etc., showing promising applications of molecular modelling and AI in the development of AD therapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6526-6552"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Learn from nature, surpass nature: Bionic immune cell engineering—A new paradigm for unlocking the dual “delivery-activation” code in cancer therapy 学习自然，超越自然：仿生免疫细胞工程——开启癌症治疗双重“传递-激活”密码的新范式

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2026-06-09 DOI: 10.1016/j.apsb.2026.06.014

Guanyi Chen, Baohu Li, Shenghua Gao, Jinfei Yang, Peng Zhan

引用次数: 0

Identification and characterization of a non-nucleotide RdRp allosteric inhibitor with pan-coronavirus protection 具有泛冠状病毒保护作用的非核苷酸RdRp变构抑制剂的鉴定与表征

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2026-03-10 DOI: 10.1016/j.apsb.2026.03.008

Qian Guo, Xiaomeng Yang, Zhihao Zhao, Jian-Piao Cai, Liang Wei, Kaiming Tang, Wan-Mui Chan, Allen Wing-Ho Chu, Yixin Huang, Tong-Yun Wang, Yubin Xie, Yulan Liu, Zi-Wei Ye, Tao Ni, Hin Chu, Jasper Fuk-Woo Chan, Kelvin Kai-Wang To, Kwok-Yung Yuen, Ying-Chih Chiang, Shuofeng Yuan

{"title":"Identification and characterization of a non-nucleotide RdRp allosteric inhibitor with pan-coronavirus protection","authors":"Qian Guo, Xiaomeng Yang, Zhihao Zhao, Jian-Piao Cai, Liang Wei, Kaiming Tang, Wan-Mui Chan, Allen Wing-Ho Chu, Yixin Huang, Tong-Yun Wang, Yubin Xie, Yulan Liu, Zi-Wei Ye, Tao Ni, Hin Chu, Jasper Fuk-Woo Chan, Kelvin Kai-Wang To, Kwok-Yung Yuen, Ying-Chih Chiang, Shuofeng Yuan","doi":"10.1016/j.apsb.2026.03.008","DOIUrl":"10.1016/j.apsb.2026.03.008","url":null,"abstract":"<div><div>The viral RNA-dependent RNA polymerase (RdRp) is a conserved and compelling target for pan-coronavirus antiviral development. To date, all US Food and Drug Administration (FDA)-approved RdRp inhibitors are nucleotide inhibitors (NIs), which are prone to drug resistance and show limited clinical efficacy. Developing alternative non-nucleotide inhibitors (NNIs) with high target specificity, structural diversity, and metabolic stability could yield more effective antivirals. Here, we identify an allosteric RdRp NNI, BAY-850, <em>via</em> computational screening. BAY-850 exhibits potent, broad-spectrum antiviral activity against multiple SARS-CoV-2 variants and other human coronaviruses. Mechanistic studies show that BAY-850 binds directly to a previously unrecognized allosteric site on nsp12, thereby fine-tuning the catalytic motif F loop out-conformation the orthosteric site. Importantly, therapeutic administration of BAY-850 significantly reduces viral loads in the nasal turbinates and lungs of SARS-CoV-2-infected K18-hACE2 mice. These findings validate a novel allosteric site in RdRp and support BAY-850 as a start-point for broad-spectrum anti-coronavirus development.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 6799-6813"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149204673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of cardiomyocytic FOXP3 and extracellular vesicle-mediated delivery of FOXP3 into cardiomyocytes for treating pathological cardiac hypertrophy 心肌细胞FOXP3和细胞外囊泡介导的FOXP3进入心肌细胞治疗病理性心肌肥大的作用

IF 14.6 1区医学

Acta Pharmaceutica Sinica. B Pub Date : 2026-10-01 Epub Date: 2025-11-18 DOI: 10.1016/j.apsb.2025.11.024

Jiahui Hong, Ping Tan, Yao Yuan, Zikun Lin, Wenjun Shan, Ya Liu, Haigang Zhang

{"title":"The role of cardiomyocytic FOXP3 and extracellular vesicle-mediated delivery of FOXP3 into cardiomyocytes for treating pathological cardiac hypertrophy","authors":"Jiahui Hong, Ping Tan, Yao Yuan, Zikun Lin, Wenjun Shan, Ya Liu, Haigang Zhang","doi":"10.1016/j.apsb.2025.11.024","DOIUrl":"10.1016/j.apsb.2025.11.024","url":null,"abstract":"<div><div>While forkhead helix transcription factor P3 (FOXP3) is a key regulator in T cells, we previously reported its anti-hypertrophic role in cardiomyocytes. In the present study, by overexpressing FOXP3 and using RNA-seq, we found that FOXP3 suppresses pathological cardiac hypertrophy by upregulating ferritin heavy chain 1, thereby inhibiting ferroptosis. However, data from the single-RNA sequence database showed that the <em>in vivo</em> cardiomyocytes exhibit minimal <em>Foxp3</em> mRNA, despite the presence of FOXP3 protein. Here, we identified cardiac microenvironment-derived extracellular vesicles (cEVs) carrying FOXP3 protein as the source of cardiomyocytic FOXP3. Leveraging this intercellular delivery mechanism, we demonstrate that administering FOXP3<sup>+</sup> cEVs from healthy hearts mitigates isoproterenol (ISO)-induced ferroptosis and hypertrophy. Due to the impracticality of large-scale production of cEVs, we identified the Jurkat cell as an alternative source of FOXP3<sup>+</sup> EVs. The Jurkat cell-derived EVs (jEVs) increased the content of cardiomyocytic FOXP3, thereby reversing hypertrophic responses. Moreover, we engineered Jurkat cells to increase FOXP3 content in the jEVs, thereby obtaining FOXP3-enriched jEVs that exhibited superior attenuation of hypertrophy and suppression of ferroptosis compared to native EVs. These findings suggest that increasing the content of FOXP3 protein in cardiomyocytes through engineered FOXP3-enriched extracellular vesicles offers a novel strategy for treating cardiac hypertrophy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 10","pages":"Pages 7054-7074"},"PeriodicalIF":14.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147880638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0