ACS Chemical Biology最新文献

{"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, Chenglong Li","doi":"10.1021/acschembio.5c00160","DOIUrl":"10.1021/acschembio.5c00160","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1333-1346"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Introducing Our Authors.","authors":"Jen Wagner","doi":"10.1021/acschembio.5c00354","DOIUrl":"https://doi.org/10.1021/acschembio.5c00354","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"1137-1138"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332048","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}

{"title":"","authors":"Karissa C. Kenney,&nbsp;Tyler P. LaFortune,&nbsp;Sourav Majumdar,&nbsp;Edgar M. Manriquez,&nbsp;Arjun S. Pamidi,&nbsp;Courtnie S. Kom,&nbsp;Jason E. Garrido,&nbsp;Edgar S. Villa,&nbsp;Filipp Furche and Gregory A. Weiss*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Site-Specific Incorporation of Clickable d-Mannose Derivatives in the Lipopolysaccharide Core of the Pathogen <i>Brucella abortus</i>.","authors":"Marine Lacritick, Angéline Reboul, Rym Yahia Boudhar, Elodie Carlier, James W Fairman, Tanguy Scaillet, Sandhya Subramanian, Johan Wouters, Bart Staker, Xavier De Bolle, Stéphane P Vincent","doi":"10.1021/acschembio.5c00202","DOIUrl":"10.1021/acschembio.5c00202","url":null,"abstract":"<p><p><i>Brucellae</i> 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 <i>Brucella abortus</i> 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.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1382-1393"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207124","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}

{"title":"Correction to \"Characterization of the Iron-Sulfur Cluster in the NCOA4 Fragment (383-522) and Its Interaction with Ferritin\".","authors":"Ayush Srivastava, Maximilian Beyer, Colby Hladun, Rebekah Tardif, Aneeta Arshad, Costel C Darie, Yeonni Zoo, Georgia C Papaefthymiou, Liu Weijing, Rosa Viner, Paolo Arosio, Fadi Bou-Abdallah","doi":"10.1021/acschembio.5c00183","DOIUrl":"10.1021/acschembio.5c00183","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1447"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172074","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}

{"title":"","authors":"Xinyu Yang,&nbsp;Yanbei Li,&nbsp;Jingyi Zhou,&nbsp;Yuanyang Zhou,&nbsp;Kexin Lin,&nbsp;Shuqing Chu,&nbsp;Jingyi Meng,&nbsp;Xinyi Ma,&nbsp;Yuan Zhu,&nbsp;Xutong Li,&nbsp;Dan Teng*,&nbsp;Mingyue Zheng* and Sulin Zhang*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00155","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Mengqin Liu*,&nbsp;Angda Li,&nbsp;Ran An* and Xingguo Liang*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial Agent Trimethoprim Influences Chemical Interactions in Cystic Fibrosis Pathogens via the <i>ham</i> Gene Cluster.","authors":"Jiangpeiyun Jin, Atharva S Kulkarni, Andrew C McAvoy, Neha Garg","doi":"10.1021/acschembio.4c00562","DOIUrl":"10.1021/acschembio.4c00562","url":null,"abstract":"<p><p>The fungus <i>Aspergillus fumigatus</i> and the bacterium <i>Burkholderia cenocepacia</i> cause fatal respiratory infections in immunocompromised humans and patients with lung disease, such as cystic fibrosis (CF). In dual infections, antagonistic interactions contribute to increased mortality. These interactions are further altered by the presence of antimicrobial and antifungal agents. However, studies performed to date on chemical interactions between clinical <i>B. cenocepacia</i> and <i>A. fumigatus</i> have focused on pathogens in isolation and do not include the most abundant chemical signal, i.e., clinically administered therapeutics, present in the lung. Here, we characterize small molecule-mediated interactions between <i>B. cenocepacia</i> and <i>A. fumigatus</i> and their shift in response to trimethoprim exposure by using metabolomics and mass spectrometry imaging. Using these methods, we report that the production of several small-molecule natural products of both the bacteria and the fungus is affected by cocultivation and exposure to trimethoprim. By systematic analysis of metabolomics data, we hypothesize that the <i>B. cenocepacia</i>-encoded <i>ham</i> gene cluster plays a role in the trimethoprim-mediated alteration of bacterial-fungal interactions. We support our findings by generating a genetically modified strain lacking the <i>ham</i> gene cluster and querying its interaction with <i>A. fumigatus</i>. Using comparative analyses of the extracts of wild-type and knockout strains, we report the inactivation of a bacterially produced antifungal compound, fragin, by <i>A. fumigatus</i>, which was verified by the addition of purified fragin to the <i>A. fumigatus</i> culture. Furthermore, we report that trimethoprim does not inhibit fungal growth, but affects the biochemical pathway for DHN-melanin biosynthesis, an important antifungal drug target, altering the pigmentation of the fungal conidia and is associated with modification of ergosterol to ergosteryl-3β-O-l-valine in coculture. This study demonstrates the impact of therapeutics on shaping microbial and fungal metabolomes, which influence interkingdom interactions and the expression of virulence factors. Our findings enhance the understanding of the complexity of chemical interactions between therapeutic compounds, bacteria, and fungi and may contribute to the development of selective treatments.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1153-1170"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibitors of the PqsR Quorum-Sensing Receptor Reveal Differential Roles for PqsE and RhlI in Control of Phenazine Production.","authors":"Julie S Valastyan, Emilee E Shine, Robert A Mook, Bonnie L Bassler","doi":"10.1021/acschembio.5c00114","DOIUrl":"10.1021/acschembio.5c00114","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> is a leading cause of hospital-acquired infections and it is resistant to many current antibiotic therapies, making development of new antimicrobial treatments imperative. The cell-to-cell communication process called quorum sensing controls <i>P. aeruginosa</i> pathogenicity. Quorum sensing relies on the production, release, and group-wide detection of extracellular signal molecules called autoinducers. Quorum sensing enables bacteria to synchronize group behaviors. <i>P. aeruginosa</i> possesses multiple quorum-sensing systems that control overlapping regulons, including some required for virulence and biofilm formation. Interventions that target <i>P. aeruginosa</i> quorum-sensing receptors are considered a fruitful avenue to pursue for new therapeutic advances. Here, we developed a <i>P. aeruginosa</i> strain that carries a bioluminescent reporter fused to a target promoter that is controlled by two <i>P. aeruginosa</i> quorum-sensing receptors. The receptors are PqsR, which binds and responds to the autoinducer called PQS (2-heptyl-3-hydroxy-4(1<i>H</i>)-quinolone) and RhlR, which binds and responds to the autoinducer called C4-HSL (C4-homoserine lactone). We used this reporter strain to screen >100,000 compounds with the aim of identifying inhibitors of either or both the PqsR and RhlR quorum-sensing receptors. We report results for 30 PqsR inhibitors from this screen. All of the identified compounds inhibit PqsR with IC₅₀ values in the nanomolar to low micromolar range and they are readily docked into the autoinducer binding site of the PqsR crystal structure, suggesting they function competitively. The majority of hits identified are not structurally related to previously reported PqsR inhibitors. Recently, RhlR was shown to rely on the accessory protein PqsE for full function. Specifically, RhlR controls different subsets of genes depending on whether or not it is bound to PqsE, however, the consequences of differential regulation on the quorum-sensing output response have not been defined. PqsR regulates <i>pqsE</i>. That feature of the system enabled us to exploit our new set of PqsR inhibitors to show that RhlR requires PqsE to activate the biosynthetic genes for pyocyanin, a key <i>P. aeruginosa</i> virulence factor, while C4-HSL is dispensable. These results highlight the promise of inhibition of PqsR as a possible <i>P. aeruginosa</i> therapeutic to suppress production of factors under RhlR-PqsE control.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1273-1287"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143950966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Z-DNA Formation in the Hybrid between Two Circular ssDNAs Involving Hairpin Structures.","authors":"Mengqin Liu, Angda Li, Ran An, Xingguo Liang","doi":"10.1021/acschembio.5c00185","DOIUrl":"10.1021/acschembio.5c00185","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1371-1381"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109039","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}