ACS Chemical Biology最新文献_第2页

Small-Molecule Inhibitors of Cholesterol Sulfotransferase as Immunomodulatory Agents. 小分子胆固醇磺酸转移酶抑制剂作为免疫调节剂。

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-28 DOI: 10.1021/acschembio.6c00658

Lindsay E Boudreau, Amanda J Smith, Hyang Yeon Lee, Bidisha Chakraborty, Kyle R Abo, Kenneth Chen, Satish K Nair, Paul J Hergenrother

引用次数: 0

Oxidized 5-Methylcytosines and Nucleosome Architecture Cooperatively Influence Thymine DNA Glycosylase Activity. 氧化5-甲基胞嘧啶和核小体结构协同影响胸腺嘧啶DNA糖基酶活性。

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-28 DOI: 10.1021/acschembio.6c00705

Allison M Goetz, Jonathan T Sczepanski

{"title":"Oxidized 5-Methylcytosines and Nucleosome Architecture Cooperatively Influence Thymine DNA Glycosylase Activity.","authors":"Allison M Goetz, Jonathan T Sczepanski","doi":"10.1021/acschembio.6c00705","DOIUrl":"https://doi.org/10.1021/acschembio.6c00705","url":null,"abstract":"Active DNA demethylation is a fundamental epigenetic process in which the iterative oxidation of 5-methylcytosine (5mC) by TET dioxygenases generates diverse combinations of oxidized 5-methylcytosines within CpG dinucleotides before their excision by thymine DNA glycosylase (TDG). Although heterogeneous CpG oxidation states are expected to arise frequently during this process, how the modification state of the opposing cytosine influences TDG activity remains poorly understood. Here, we developed a chemically defined panel of CpG substrates containing cytosine, 5mC, 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) opposite a target 5fC and systematically examined TDG-mediated excision in both naked DNA and nucleosome core particles (NCPs). In naked DNA, opposing-strand cytosine modifications exerted only modest effects on TDG activity when a single excisable base was present within the CpG dyad, whereas dual-substrate CpGs exhibited unexpected differences in strand utilization. In contrast, nucleosome assembly profoundly altered TDG activity, revealing modification-dependent effects that were largely absent in naked DNA and dramatically redistributing strand utilization within dual-substrate CpGs. Together, these findings demonstrate that the oxidation-state composition of a CpG dyad and nucleosome architecture cooperatively regulate TDG activity, establishing heterogeneous CpG oxidation states as functionally distinct substrates for TDG and providing a biochemical framework for understanding how chromatin structure regulates active DNA demethylation.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284203","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

Conjugation of a Cell-Penetrating Peptide to the Lasso Peptides Citrocin and Microcin J25 Enhances Antimicrobial Activity. 细胞穿透肽与套索肽Citrocin和Microcin J25偶联增强抗菌活性。

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-27 DOI: 10.1021/acschembio.6c00723

Alina Thokkadam, Dean M Miller, Tiziana Svenningsen, Si Jia Pan, Thomas Tørring, A James Link

{"title":"Conjugation of a Cell-Penetrating Peptide to the Lasso Peptides Citrocin and Microcin J25 Enhances Antimicrobial Activity.","authors":"Alina Thokkadam, Dean M Miller, Tiziana Svenningsen, Si Jia Pan, Thomas Tørring, A James Link","doi":"10.1021/acschembio.6c00723","DOIUrl":"https://doi.org/10.1021/acschembio.6c00723","url":null,"abstract":"A subset of lasso peptides function as antibiotics against Gram-negative bacteria by inhibition of the bacterial RNA polymerase (RNAP), including microcin J25 (MccJ25) and citrocin. These peptides interact with specific transporters in the inner and outer membranes of bacteria to gain access to the cytoplasm. The reliance on transporters limits the breadth of spectrum of these lasso peptide antibiotics and opens up paths to drug resistance. Here, we detail a strategy to overcome the transport limitations of lasso peptides: covalent conjugation of the lasso peptide to a cell penetrating peptide (CPP). Citrocin-CPP and MccJ25-CPP conjugates were synthesized by attaching the CPP to the loop of the lasso peptide and tested for antimicrobial activity against the ESKAPE pathogens. Citrocin-CPP and MccJ25-CPP have antimicrobial activity against all four Gram-negative ESKAPE pathogens, a broader spectrum of activity than the parent lasso peptides. Citrocin-CPP and MccJ25-CPP also exhibit more potent activity than the parent lasso peptides, with minimum inhibitory concentrations in the high nanomolar to single micromolar range. The uptake of citrocin-CPP and MccJ25-CPP was also studied in Escherichia coli revealing that the conjugates are internalized via both transporter-dependent and transporter-independent pathways.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259616","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

Site-Selective Bioconjugations of Distinct Methionine Residues in a Protein via Reactivity-Based Reagent Control. 通过基于反应性的试剂控制，蛋白质中不同蛋氨酸残基的位点选择性生物偶联。

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-27 DOI: 10.1021/acschembio.6c00636

Elizabeth J Sisko, Kaan Kumru, James A Wells, Jason K Sello

{"title":"Site-Selective Bioconjugations of Distinct Methionine Residues in a Protein via Reactivity-Based Reagent Control.","authors":"Elizabeth J Sisko, Kaan Kumru, James A Wells, Jason K Sello","doi":"10.1021/acschembio.6c00636","DOIUrl":"https://doi.org/10.1021/acschembio.6c00636","url":null,"abstract":"The reaction of thioethers in biological macromolecules with oxaziridines enables their functionalization with moieties having utility in both basic and applied science. Exploitation of that reaction has advantages over common bioconjugations due to the relatively low abundance and weak reactivity of thioethers. Herein, we report a novel and improved route to 1-ureal piperidine,3-aryl oxaziridines that enables the preparation of bioconjugation reagents that are either electronically activated or deactivated. We leveraged the differential reactivities of the oxaziridine reagents and engineered methionine residues in distinct environments within a therapeutically relevant antibody fragment (Fab) to effect site-selective bioconjugations. We capitalized on this novel means of kinetic resolution to effect dual functionalization of a HER2-targeted Fab with distinct fluorophores for imaging receptor internalization. This work broadens the scope of what is possible in bioconjugations of thioethers and demonstrates that site-selective bioconjugations of the same residue at more than one site in a protein can be realized via reactivity-based reagent control.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259633","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

Pharmacological ON/OFF Regulation of CAR T Cells through Estrogen Receptor-Based Stabilization and Targeted Degradation. 基于雌激素受体稳定和靶向降解的CAR - T细胞的药理开/关调控。

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-27 DOI: 10.1021/acschembio.6c00722

Erik Rihtar, Tina Fink, Monika Belak, Rebeka Udvanc, Roman Jerala

{"title":"Pharmacological ON/OFF Regulation of CAR T Cells through Estrogen Receptor-Based Stabilization and Targeted Degradation.","authors":"Erik Rihtar, Tina Fink, Monika Belak, Rebeka Udvanc, Roman Jerala","doi":"10.1021/acschembio.6c00722","DOIUrl":"https://doi.org/10.1021/acschembio.6c00722","url":null,"abstract":"Regulation of therapeutic cell response is important for safe and effective therapy, particularly for immunotherapy. Ideally, the regulators should be based on human proteins using compounds that have already been approved for human use. Regulation of protein degradation by small molecules enables fast cellular response and a small genetic footprint of genetic constructs. Here, we present a clinically compatible strategy for reversible pharmacological control of chimeric antigen receptor (CAR) T cell function using human estrogen receptor (ER)-based degron domains and FDA-approved small molecules. By fusing tamoxifen-responsive ER ligand-binding domains to CARs, we generate ligand-inducible ON-switch CARs whose stability, signaling, and effector functions are precisely controlled by 4-hydroxytamoxifen. Furthermore, we demonstrate that ER-tagged CARs can be selectively degraded using the FDA-approved ER-targeting PROTAC ARV-471, establishing a complementary OFF-switch mechanism that suppresses CAR expression and effector function. Notably, these results expand the ON-OFF switch platform for post-translational control of therapeutic proteins, offering new opportunities to improve the safety and precision of cellular immunotherapies.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284216","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

G-Tract Length Shapes the Fate of G-Quadruplexes. g束长度决定g -四联体的命运。

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-27 DOI: 10.1021/acschembio.6c00664

Jiahang Zhou, Jianjun Xia, Petr Stadlbauer, Mingpan Cheng, Shijiong Wei, Xinrong Yan, Xinzhe Zhuang, Huangxian Ju, Jiří Šponer, Jean-Louis Mergny, David Monchaud, Jun Zhou

{"title":"G-Tract Length Shapes the Fate of G-Quadruplexes.","authors":"Jiahang Zhou, Jianjun Xia, Petr Stadlbauer, Mingpan Cheng, Shijiong Wei, Xinrong Yan, Xinzhe Zhuang, Huangxian Ju, Jiří Šponer, Jean-Louis Mergny, David Monchaud, Jun Zhou","doi":"10.1021/acschembio.6c00664","DOIUrl":"https://doi.org/10.1021/acschembio.6c00664","url":null,"abstract":"Guanine (G)-rich DNA sequences can form unusual secondary structures known as G-quadruplexes (or G4s). The stability of these structures, whose folding is mainly driven by the formation and stacking of G-quartets, is influenced by several factors, foremost among them the nature of the sequence itself, particularly the nucleobases flanking the G-tracts, and the loops connecting them. A considerable effort has been devoted to understanding how the size, position, and composition of each loop and flanking sequences affect the stability of the resulting G4 fold. However, most of these studies have been restricted to sequences forming a three G-quartet G4 core. To better understand how the length of the G-tracts (from three to five Gs) and loops (from one to seven nucleotides) act in concert, we studied a set of 261 different sequences covering different possible combinations. A systematic biophysical analysis suggests that sequences with longer G-tracts tend to form more stable G4s, but also a mixture of species; it further shows that loop composition and position also influence the topology and stability of the resulting G4s. Collectively, this work provides an unprecedented view on how G4-forming sequences fold upon themselves and of the structural features that govern the stability of the resulting G4s.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259600","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

A Biocompatible Cu(I)-Catalyzed Click Chemistry Framework for Long-Term Cell Tracking. 用于长期细胞跟踪的生物相容性Cu(I)催化点击化学框架。

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-26 DOI: 10.1021/acschembio.6c00610

Alex H Chen, Yingzhao Zhao, Soojin Kwon, Rashmi Vyas, Raymond F Gamache, Tiantian Sun, Hasan Babazada, Katheryn Lohith, Michael D Farwell

引用次数: 0

A Modular Optogenetic Split-Small GTPase Platform Reveals Long-Range RhoA Signaling. 模块化光遗传分裂-小GTPase平台揭示远程RhoA信号。

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-23 DOI: 10.1021/acschembio.6c00691

Benjamin Faulkner, Yuchen He, Daniel Sitrin, Linda Ziamanesh, Cliff I Stains

{"title":"A Modular Optogenetic Split-Small GTPase Platform Reveals Long-Range RhoA Signaling.","authors":"Benjamin Faulkner, Yuchen He, Daniel Sitrin, Linda Ziamanesh, Cliff I Stains","doi":"10.1021/acschembio.6c00691","DOIUrl":"https://doi.org/10.1021/acschembio.6c00691","url":null,"abstract":"Small GTPases are critical regulators of cellular processes such as cell migration. However, no generalizable method exists for directly controlling their activity with subcellular precision, limiting the ability to dissect long-range signaling effects. To address this, we pair fragmented small GTPases with improved light-inducible dimerization (iLID) domains, optimizing for low dark-state background and efficient light-induced reassembly, affording spLIT-small GTPases. Demonstrating modularity, we control filopodia formation (spLIT-Cdc42), cell movement (spLIT-Rac1), and membrane retraction (spLIT-RhoA) with subcellular precision. Applying this platform to long-range signaling, we provide the first demonstration that localized RhoA activation is sufficient to drive membrane retraction at the opposite cell pole, with a directional dependence set by actin cytoskeleton polarization, a result inaccessible to global perturbations used previously. These results suggest a mechanism for coordinated establishment of cell polarity and highlight spLIT-small GTPases as a versatile platform for the direct, spatial control of small GTPase signaling in living cells.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259613","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

Characterization of Chromone Biosynthetic Pathway Reveals a Noncanonical Mode of Fungal Polyketide Cyclization. 色素生物合成途径的表征揭示了真菌聚酮环化的非规范模式。

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-22 DOI: 10.1021/acschembio.6c00730

Sydney Choi, Brandon Wong, Zuodong Sun, Yi Tang

{"title":"Characterization of Chromone Biosynthetic Pathway Reveals a Noncanonical Mode of Fungal Polyketide Cyclization.","authors":"Sydney Choi, Brandon Wong, Zuodong Sun, Yi Tang","doi":"10.1021/acschembio.6c00730","DOIUrl":"https://doi.org/10.1021/acschembio.6c00730","url":null,"abstract":"Fungal nonreducing polyketide synthases (NRPKSs) produce therapeutically and ecologically important aromatic polyketides. The product template (PT) domain of fungal NRPKSs catalyzes the regioselective aldol cyclization of the reactive poly-β-ketone chain during polyketide maturation and is essential for product fidelity of the NRPKSs. Herein, we discovered the fungal NRPKS MecA of which the polyketide cyclization steps do not involve a functional PT domain. MecA is encoded in the biosynthetic gene cluster (BGC) responsible for the formation of 5-hydroxy-7-methoxy-2,3-dimethylchromone (1) from the biocontrol fungus Trichoderma afroharzianum T22. Heterologous expression and in vitro enzymatic assays fully established a biosynthetic pathway of 1 that involves three enzymes: MecA, dehydratase MecB, and methyltransferase MecC. The PT domain of MecA does not contain the conserved catalytic histidine that is essential for aldol cyclization activity. Consistent with the predicted inactive PT domain, MecA was demonstrated to catalyze a C1-C6 Claisen condensation as the first cyclization step of the pentaketide precursor, instead of the canonical aldol cyclization. Reconstitution of dissected MecA domains further demonstrated that the activity of MecA was not affected when the PT domain was removed. A Claisen Cyclase (CLC) domain that typically catalyzes Claisen cyclization in NRPKSs is also absent in MecA, implying the observed C1-C6 cyclization step is catalyzed by the remaining domains. This work contributes to the diversity of NRPKS cyclization chemistry and enables further genome mining and engineering of NRPKSs that may lead to biosynthesis of new aromatic polyketides.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149242153","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

Improving PROTAC-Mediated Degradation in Mouse Models: BRD9 as a Case Study. 改善protac介导的小鼠模型降解：BRD9为例研究

IF 3.6 2区生物学

ACS Chemical Biology Pub Date : 2026-10-21 DOI: 10.1021/acschembio.6c00628

Brayden P Strohmier, Jude T Quarshie, Rinky Raghuvanshi, Sukhmandeep Kaur, Gabriella G Conjelko, Emily C Dykhuizen

{"title":"Improving PROTAC-Mediated Degradation in Mouse Models: BRD9 as a Case Study.","authors":"Brayden P Strohmier, Jude T Quarshie, Rinky Raghuvanshi, Sukhmandeep Kaur, Gabriella G Conjelko, Emily C Dykhuizen","doi":"10.1021/acschembio.6c00628","DOIUrl":"https://doi.org/10.1021/acschembio.6c00628","url":null,"abstract":"Proteolysis-targeting chimeras (PROTACs) have emerged as powerful chemical tools and therapeutics, yet their translation from preclinical models to humans remains inconsistent. Here, we systematically evaluate the activity of BRD9-targeting PROTACs in human and mouse systems to elucidate a key limitation in preclinical studies. Widely used CRBN- and VHL-recruiting degraders, including dBRD9 and VZ185, exhibit markedly reduced potency in mouse cells despite high sequence conservation of BRD9. Mechanistic interrogation reveals that species-specific differences in E3 ligases, particularly the Crbn I391 residue and structural variations in VHL, likely impair productive ternary complex formation. Expression of human CRBN or VHL, or introduction of the CrbnI391V mutation, increases degradation potency in mouse cells. Importantly, in vivo studies demonstrate enhanced BRD9 degradation in CrbnI391V mice using clinically relevant degraders. These findings highlight a critical barrier in PROTAC evaluation and establish humanized E3 ligase models as tools for more accurate assessment of on-target efficacy and toxicity.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236240","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