ACS Chemical Biology最新文献_第9页

Site-Specific Incorporation of Clickable d-Mannose Derivatives in the Lipopolysaccharide Core of the Pathogen Brucella abortus 可点击d-甘露糖衍生物在流产布鲁氏菌脂多糖核中的位点特异性结合

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-06-03 DOI: 10.1021/acschembio.5c0020210.1021/acschembio.5c00202

Marine Lacritick, Angéline Reboul, Rym Yahia Boudhar, Elodie Carlier, James W. Fairman, Tanguy Scaillet, Sandhya Subramanian, Johan Wouters, Bart Staker, Xavier De Bolle* and Stéphane P. Vincent*,

{"title":"Site-Specific Incorporation of Clickable d-Mannose Derivatives in the Lipopolysaccharide Core of the Pathogen Brucella abortus","authors":"Marine Lacritick, Angéline Reboul, Rym Yahia Boudhar, Elodie Carlier, James W. Fairman, Tanguy Scaillet, Sandhya Subramanian, Johan Wouters, Bart Staker, Xavier De Bolle* and Stéphane P. Vincent*, ","doi":"10.1021/acschembio.5c0020210.1021/acschembio.5c00202","DOIUrl":"https://doi.org/10.1021/acschembio.5c00202https://doi.org/10.1021/acschembio.5c00202","url":null,"abstract":"Brucellae are pathogenic bacteria responsible for a worldwide zoonosis called brucellosis. In this study, we exploit the d-mannose central metabolism for the selective labeling of lipopolysaccharide (LPS), a key virulence factor in Gram-negative bacteria. Our approach provides chemical tools to allow selective derivatization of bacterial membranes in vivo and a handle for imaging studies. Using Brucella abortus mutants, we demonstrate that the clickable monosaccharides are exclusively incorporated into the lateral branch of the core LPS glycan but not in the O-chain or any other cell wall component. The metabolic route followed by the mannose analogues was also evidenced and showed that phosphomutase ManB, whose XRD 3D-structure was solved, was the metabolic entry of azidosugars, which do not follow a salvage pathway. Site-specific incorporation of mannose in the LPS core opens new perspectives such as the identification of macromolecules binding this important structure for the host–pathogen interaction.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1382–1393 1382–1393"},"PeriodicalIF":3.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Novel Lipophagy Inducers as Potential Therapeutics for Lipid Metabolism Disorders 新型脂噬诱导剂作为脂代谢紊乱的潜在治疗药物

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-06-02 DOI: 10.1021/acschembio.5c0021210.1021/acschembio.5c00212

Rachel Njeim, Bassel Awada, Haley Donow, Haley Gye, Cole Foster, Colin Kelly, Judith Molina, Sandra Merscher, Marcello Giulianotti, Alessia Fornoni and Hassan Al-Ali*,

{"title":"Novel Lipophagy Inducers as Potential Therapeutics for Lipid Metabolism Disorders","authors":"Rachel Njeim, Bassel Awada, Haley Donow, Haley Gye, Cole Foster, Colin Kelly, Judith Molina, Sandra Merscher, Marcello Giulianotti, Alessia Fornoni and Hassan Al-Ali*, ","doi":"10.1021/acschembio.5c0021210.1021/acschembio.5c00212","DOIUrl":"https://doi.org/10.1021/acschembio.5c00212https://doi.org/10.1021/acschembio.5c00212","url":null,"abstract":"Dysregulation of lipid homeostasis is associated with a wide range of pathologies encompassing neurological, metabolic, cardiovascular, oncological, and renal disorders. We previously showed that lipid droplet (LD) accumulation in podocytes contributes to the progression of diabetic kidney disease (DKD) and reducing LDs preserves podocyte function and prevents albuminuria. Here, we sought to identify compounds that treat pathological LD accumulation. We developed a phenotypic assay using human podocytes and deployed it to screen a combinatorial library comprising over 45 million unique small molecules. This led to the identification of a compound series that effectively reduces LD accumulation in stressed podocytes. Mechanistic studies revealed that these compounds activate lipophagy, reduce LD accumulation, and rescue podocytes from cell death. In contrast, compounds known to induce general autophagy failed to mimic these effects, indicating a novel lipophagy-specific mechanism of action (MoA), which was confirmed by unbiased phenotypic profiling. An advantage of this therapeutic strategy is its potential to not only halt the progression of pathological lipid accumulation but also reverse it. These compounds will serve as tools for uncovering novel drug targets and therapeutic MoAs for treating DKD and other diseases with similar etiologies.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1406–1416 1406–1416"},"PeriodicalIF":3.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery and Mechanism of 16–19F, a Novel Synthetic Lethal Inhibitor of the PRMT5•MTA Complex in MTAP-Deleted Cancer Cells mtap缺失癌细胞中PRMT5•MTA复合物的新型合成致死抑制剂16-19F的发现及其机制

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-05-29 DOI: 10.1021/acschembio.5c0016010.1021/acschembio.5c00160

Zhihang Shen, Xiaozhi Yang, Gustavo Seabra, Xueyong Xu, Jiawei Dong, Jason Orr Brant, Wei Zhou, Juan Guan, Wen Jiang and Chenglong Li*,

{"title":"Discovery and Mechanism of 16–19F, a Novel Synthetic Lethal Inhibitor of the PRMT5•MTA Complex in MTAP-Deleted Cancer Cells","authors":"Zhihang Shen, Xiaozhi Yang, Gustavo Seabra, Xueyong Xu, Jiawei Dong, Jason Orr Brant, Wei Zhou, Juan Guan, Wen Jiang and Chenglong Li*, ","doi":"10.1021/acschembio.5c0016010.1021/acschembio.5c00160","DOIUrl":"https://doi.org/10.1021/acschembio.5c00160https://doi.org/10.1021/acschembio.5c00160","url":null,"abstract":"Protein arginine methyltransferase 5 (PRMT5), which uniquely binds to 5′-methylthioadenosine (MTA) among the PRMT family, is emerging as an attractive epigenetic target for 5′-methylthioadenosine phosphorylase (MTAP)-deleted cancer treatments. Here, we report the discovery of a novel inhibitor 16–19F, which is a potent binder to the PRMT5•MTA, PRMT5•SAH, and PRMT5•SAM complexes and selectively inhibited MTAP-deleted cancer cell growth. Based on transcriptome analysis, we found that kinetochore metaphase signaling and cell cycle control of the chromosomal replication pathway were downregulated after 16–19F treatment in the MDA-MB-231 TNBC cell line. Additionally, we identified a new PRMT5 substrate, MCM7, an important component of DNA helicase, and figured out the potential methylation site Arg219 by site-directed mutagenesis and computational analysis. Moreover, we showed that 16–19F treatment regulated MCM7 localization, which is involved through liquid–liquid phase separation mechanisms, including the formation of stress granules. Together, we discovered a potential novel drug candidate and revealed an unknown mechanism in which PRMT5 methylation altered MCM7 localization by modulating stress granule formation.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1333–1346 1333–1346"},"PeriodicalIF":3.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Correction to “Characterization of the Iron–Sulfur Cluster in the NCOA4 Fragment (383–522) and Its Interaction with Ferritin” 修正“NCOA4片段（383-522）中铁硫团簇的表征及其与铁蛋白的相互作用”

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-05-29 DOI: 10.1021/acschembio.5c0018310.1021/acschembio.5c00183

Ayush Srivastava, Maximilian Beyer, Colby Hladun, Rebekah Tardif, Aneeta Arshad, Costel C. Darie, Yeonni Zoo, Georgia C. Papaefthymiou, Liu Weijing, Rosa Viner, Paolo Arosio and Fadi Bou-Abdallah*,

引用次数: 0

Phage Display Selection against a Mixture of Protein Targets 针对混合蛋白靶标的噬菌体展示选择

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-05-26 DOI: 10.1021/acschembio.5c0012110.1021/acschembio.5c00121

Xu-Dong Kong*, Meng-Jie Zhang and Christian Heinis*,

{"title":"Phage Display Selection against a Mixture of Protein Targets","authors":"Xu-Dong Kong*, Meng-Jie Zhang and Christian Heinis*, ","doi":"10.1021/acschembio.5c0012110.1021/acschembio.5c00121","DOIUrl":"https://doi.org/10.1021/acschembio.5c00121https://doi.org/10.1021/acschembio.5c00121","url":null,"abstract":"Affinity selections by phage display or other display techniques are typically performed against single targets immobilized as a purified protein. In order to develop cross-specific binders that engage with multiple proteins, such as members of a related family, we herein propose to perform selections against mixtures of proteins as bait. Combined with follow-up selection rounds against the individual proteins, deep sequencing, and single clone enrichment analysis, we expected to distinguish binders that are cross-specific from those that are not. Indeed, applying the strategy to human and mouse coagulation factor XI (hFXI and mFXI), and thus to a situation with limited complexity due to a mixture of only two targets, allowed rapid identification of peptide-based binders along with precise information about their specificity. The study also provided insights into the dynamics and challenges of multitarget affinity selections, showing that one target can easily dominate the selection process and hinder the enrichment of binders to other proteins in a mixture.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1288–1297 1288–1297"},"PeriodicalIF":3.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Discovery and Identification of a Novel PORCN Inhibitor via Structure-Based Virtual Screening 基于结构虚拟筛选的新型PORCN抑制剂的发现和鉴定

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-05-26 DOI: 10.1021/acschembio.5c0015510.1021/acschembio.5c00155

Xinyu Yang, Yanbei Li, Jingyi Zhou, Yuanyang Zhou, Kexin Lin, Shuqing Chu, Jingyi Meng, Xinyi Ma, Yuan Zhu, Xutong Li, Dan Teng*, Mingyue Zheng* and Sulin Zhang*,

{"title":"Discovery and Identification of a Novel PORCN Inhibitor via Structure-Based Virtual Screening","authors":"Xinyu Yang, Yanbei Li, Jingyi Zhou, Yuanyang Zhou, Kexin Lin, Shuqing Chu, Jingyi Meng, Xinyi Ma, Yuan Zhu, Xutong Li, Dan Teng*, Mingyue Zheng* and Sulin Zhang*, ","doi":"10.1021/acschembio.5c0015510.1021/acschembio.5c00155","DOIUrl":"https://doi.org/10.1021/acschembio.5c00155https://doi.org/10.1021/acschembio.5c00155","url":null,"abstract":"Dysregulated activation of the Wnt pathway is closely associated with oncogenesis and the progression of various cancers. Palmitoylation catalyzed by porcupine (PORCN) is essential for the secretion of Wnts and the activation of the Wnt pathway. Given its critical role in regulating Wnt signaling, PORCN has been recognized as a promising therapeutic target for cancers driven by aberrant Wnt pathway activation. Herein, we explored the binding modes of reported inhibitors with different scaffolds using molecular docking and molecular dynamics simulations, establishing an optimized structure-based virtual screening model, which discovered a novel PORCN inhibitor, Y-99. Y-99 demonstrated promising inhibitory activity against the Wnt/β-catenin signaling pathway (IC50 = 155.4 nM) and exhibited high binding affinity to PORCN (KD = 33.1 nM). Notably, Y-99 exerted a significant antiproliferation effect in Wnt-addicted tumor cell lines, accompanied by reduced LRP6 phosphorylation and downregulation of Wnt-related gene expression, including AXIN2 and CCND1. Taken together, these findings highlight that Y-99, which was identified through in silico screening and validated in vitro, is a promising PORCN inhibitor, which has the potential for further research and development.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1319–1332 1319–1332"},"PeriodicalIF":3.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Z-DNA Formation in the Hybrid between Two Circular ssDNAs Involving Hairpin Structures 涉及发夹结构的两个环状ssdna杂交中Z-DNA的形成

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-05-21 DOI: 10.1021/acschembio.5c0018510.1021/acschembio.5c00185

Mengqin Liu*, Angda Li, Ran An* and Xingguo Liang*,

{"title":"Z-DNA Formation in the Hybrid between Two Circular ssDNAs Involving Hairpin Structures","authors":"Mengqin Liu*, Angda Li, Ran An* and Xingguo Liang*, ","doi":"10.1021/acschembio.5c0018510.1021/acschembio.5c00185","DOIUrl":"https://doi.org/10.1021/acschembio.5c00185https://doi.org/10.1021/acschembio.5c00185","url":null,"abstract":"Z-DNA, a left-handed DNA conformation, plays critical roles in transcriptional regulation, genetic recombination, genomic instability, immunity, and human diseases. In 2019, a stable LR-chimera containing Z-DNA (Lk = 0) under physiological ionic conditions was prepared by hybridizing two complementary circular ssDNAs. However, the difficulty in preparing circular ssDNA precursors and the excessively long Z-DNA segment in the chimera limit its applications. In this study, using a splint-free circularization method, we prepared two circular ssDNAs (each with a hairpin structure). Hybridization of these two circles whose loops are complementary (but not the two hairpins) yielded a Stem-LR chimera containing short Z-DNA and B-DNA and two hairpins that could not hybridize with each other. Stability analysis revealed that the 18–34 bp Z-DNA segment with only unmodified nucleotides in the Stem-LR chimera remained stable under physiological conditions (10 mM Mg2+, 37 °C). When hairpins were far apart (180°), multiple Stem-LR chimera isomers (varying in B–Z junction numbers and Z-DNA lengths) formed. Intriguingly, higher hybridization temperatures (60 °C) favored continuous B-DNA and Z-DNA segments (minimal B–Z junctions). When hairpins were adjacent (0° orientation), exclusively continuous B-DNA/Z-DNA was obtained, even for hybridization at 10 °C. As expected, Stem-LR chimeras exhibited enhanced resistance to topoisomerase I compared to chimeras without hairpins. This approach holds promise for delivery into cells or organisms to investigate the impact of Z-DNA and its biological functions under physiological conditions.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1371–1381 1371–1381"},"PeriodicalIF":3.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Expansion Microscopy Provides Nanoscale Insight into Nucleolar Reorganization and Nuclear Foci Formation during Nucleolar Stress 扩展显微镜提供纳米尺度的洞察核仁重组和核仁焦点形成过程中的核仁应力

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-05-20 DOI: 10.1021/acschembio.5c0010410.1021/acschembio.5c00104

Katelyn R. Alley, Katelyn M. Wyatt, Adam C. Fries and Victoria J. DeRose*,

{"title":"Expansion Microscopy Provides Nanoscale Insight into Nucleolar Reorganization and Nuclear Foci Formation during Nucleolar Stress","authors":"Katelyn R. Alley, Katelyn M. Wyatt, Adam C. Fries and Victoria J. DeRose*, ","doi":"10.1021/acschembio.5c0010410.1021/acschembio.5c00104","DOIUrl":"https://doi.org/10.1021/acschembio.5c00104https://doi.org/10.1021/acschembio.5c00104","url":null,"abstract":"The nucleolus, a membraneless organelle crucial for ribosome production, has a unique nanoscale structure whose organization is responsive to cell signals and disease progression. Here, we highlight the potential of Expansion Microscopy (ExM) for capturing intricate spatial and functional information about membraneless organelles such as the nucleolus and nuclear foci. We apply dual protein Expansion Microscopy (dual-proExM) in combination with click Expansion Microscopy (click-ExM) to capture images at the highest resolution reported for the nucleolus of ∼45 ± 2 nm. Inhibition of nucleolar processes triggers a nucleolar stress response, causing distinct structural rearrangements whose molecular basis is an area of active investigation. We investigate time-dependent changes in nucleolar structure and function under nucleolar stress induced by oxaliplatin, actinomycin D, and other platinum-based compounds. Our findings reveal new stages that occur prior to the complete sequestration of RNA Pol I into nucleolar caps, shedding light on the early mechanisms of the nucleolar stress response. RNA transcription is linked to nanoscale protein rearrangements using a combination of click-ExM and pro-ExM, revealing locations of active transcripts during the early stages of nucleolar stress reorganization. With prolonged stress, fibrillarin and NPM1 segregate from the nucleolus into nucleoplasmic foci that are for the first time imaged at nanometer resolution. In addition to revealing new morphological information about the nucleolus, this study demonstrates the potential of ExM for imaging membraneless organelles with nanometer-scale precision.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1232–1246 1232–1246"},"PeriodicalIF":3.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Protein Phosphatase 5-Recruiting Chimeras for Accelerating Tau Dephosphorylation 蛋白磷酸酶5募集嵌合体加速Tau去磷酸化

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-05-20 DOI: 10.1021/acschembio.5c0016510.1021/acschembio.5c00165

Jinying Gu, Chenxi He, Zeyu Han, Qifei Huang, Yanyi He, Yun Lu*, Qidong You*, Qiuyue Zhang* and Lei Wang*,

{"title":"Protein Phosphatase 5-Recruiting Chimeras for Accelerating Tau Dephosphorylation","authors":"Jinying Gu, Chenxi He, Zeyu Han, Qifei Huang, Yanyi He, Yun Lu*, Qidong You*, Qiuyue Zhang* and Lei Wang*, ","doi":"10.1021/acschembio.5c0016510.1021/acschembio.5c00165","DOIUrl":"https://doi.org/10.1021/acschembio.5c00165https://doi.org/10.1021/acschembio.5c00165","url":null,"abstract":"Hyperphosphorylation of proteins is implicated in various diseases, such as phosphorylated Tau (p-Tau), which is the main cause of Alzheimer’s disease (AD). Dephosphorylation strategies have still been limited. Currently, phosphatase recruitment chimeras (PHORCs) have become a potential strategy for accelerating the dephosphorylation of proteins. However, PHORCs are still in the proof-of-concept stage. The paucity of available phosphatase effectors and the lack of effective methods to identify the appropriate length of the linker impede the development of PHORCs. Protein phosphatase 5 (PP5) is responsible for dephosphorylation of p-Tau in the brain. PP5 is distinct from other phosphatases, with a unique activation mechanism. We demonstrated that PP5 can be simultaneously recruited and activated for the design of PHORCs, exhibiting a synergistic advantage for accelerating dephosphorylation of p-Tau. Moreover, we attempted computation-aided prediction methods to obtain the potential length of the linker, promoting the rational design of PHORCs. Therefore, our study provides critical insights into the development of PHORCs and proposes new ideas for accelerating the design of heterotrimeric chimeras.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1347–1360 1347–1360"},"PeriodicalIF":3.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Human PTGR2 Inactivation Alters Eicosanoid Metabolism and Cytokine Response of Inflammatory Macrophages 人PTGR2失活改变炎性巨噬细胞的类二十烷代谢和细胞因子反应

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-05-19 DOI: 10.1021/acschembio.5c0023110.1021/acschembio.5c00231

Michael W. Founds, Olivia L. Murtagh, R. Justin Grams, Zhihong Li, Anthony M. Ciancone, Robert J Seal and Ku-Lung Hsu*,

{"title":"Human PTGR2 Inactivation Alters Eicosanoid Metabolism and Cytokine Response of Inflammatory Macrophages","authors":"Michael W. Founds, Olivia L. Murtagh, R. Justin Grams, Zhihong Li, Anthony M. Ciancone, Robert J Seal and Ku-Lung Hsu*, ","doi":"10.1021/acschembio.5c0023110.1021/acschembio.5c00231","DOIUrl":"https://doi.org/10.1021/acschembio.5c00231https://doi.org/10.1021/acschembio.5c00231","url":null,"abstract":"Prostaglandin reductase 2 (PTGR2) regulates inflammatory lipid signaling through the metabolism of the PGE2 metabolite 15-keto-PGE2. PTGR2 inhibitors have been reported but whether small molecule inactivation can recapitulate the anti-inflammatory phenotype observed in PTGR2 knockout systems has not been explored. Here, we disclose an optimized sulfonyl triazole (SuTEx) inhibitor of human PTGR2 that blocks biochemical activity by liganding the noncatalytic tyrosines Y100 and Y265 in the active site. Quantitative and multiplexed chemoproteomics verified covalent engagement of endogenous PTGR2 in THP1 macrophages with moderate proteome-wide selectivity. PTGR2 inactivation with the SuTEx inhibitor resulted in suppression of secreted inflammatory lipids and TNF-α in lipopolysaccharide (LPS)-stimulated macrophages. Collectively, our findings identify a potent covalent inhibitor of human PTGR2 that can serve as a tool compound for exploring lipid metabolism and signaling in macrophages.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1426–1434 1426–1434"},"PeriodicalIF":3.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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