ChemBioChem最新文献

{"title":"Bioorthogonal Chemistry in Neurobiology: From Imaging to Proteomics","authors":"Neil Taylor,&nbsp;João de Sousa-Lourenço,&nbsp;Ivana Nikić-Spiegel","doi":"10.1002/cbic.202500949","DOIUrl":"https://doi.org/10.1002/cbic.202500949","url":null,"abstract":"<p>Bioorthogonal click chemistry has emerged as a versatile approach for probing molecules with high selectivity and minimal perturbation. While applicable to diverse biomolecules, its use in protein studies has proven particularly powerful, especially in neurobiology, where precise molecular tools are essential. A key technology enabling such precision is genetic code expansion (GCE), which allows the incorporation of unnatural amino acids (UAAs) bearing bioorthogonal handles into proteins. These UAAs can be introduced site-specifically to label defined proteins or proteome-wide for systems-level analysis. Complementing this, proteome-wide labeling can be achieved through metabolic incorporation of amino acid analogs. Coupled with copper-catalyzed or strain-promoted click reactions, these labeling technologies enable applications ranging from protein visualization to mass spectrometry-based proteomics. Ongoing advances in UAA incorporation strategies and the chemical diversity of available UAAs continue to broaden the opportunities to study protein expression, localization, and dynamics. In this review, we highlight recent methodological developments in click chemistry-based protein labeling and their applications in neurobiology.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 20","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202500949","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149177177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Binding of Zinc(II) to Apo-Metallo-β-Lactamases: Characterization by Isothermal Titration Calorimetry","authors":"Le Zhai,&nbsp;Jiazhu Chigan,&nbsp;Wen-Ming Wang,&nbsp;Jin Wang,&nbsp;Hua-Ping Xie,&nbsp;Yao Zhao,&nbsp;Yi-Qiang Wu,&nbsp;Yi-Xue Wang,&nbsp;Wei-Xing Zhao,&nbsp;Ke-Wu Yang","doi":"10.1002/cbic.70563","DOIUrl":"10.1002/cbic.70563","url":null,"abstract":"<p>Antibiotic resistance caused by metallo-β-lactamases (MβLs) is a global public health threat. In this work, we first directly investigated the binding of Zn²⁺ to apo-MβLs through isothermal titration calorimetry. It was found that carbapenem and cephamycin resistance metallo-β-lactamase (CcrA), New Delhi metallo-β-lactamase-1 (NDM-1) and <i>Stenotrophomonas maltophilia</i> Metallo-β-lactamase-1(L1) bind Zn²⁺ in a sequential mode, while imipenemase-1 (IMP-1) and Verona Integron-encoded metallo-β-lactamase-2 (VIM-2) bind Zn²⁺ in a mode of varying levels of cooperativity, in which the mononuclear species was not detectable, and also, the mode was verified through the titration of Co²⁺ into apo-VIM-2 monitored by UV–vis. The thermodynamic and kinetic parameters revealed the binding of Zn²⁺ to the active sites was independent of stoichiometry. Analysis of the parameters determined suggested that the binding of B1 and B3 MβLs to Zn²⁺ depends on the binding affinity and/or Gibbs free energy change of Zn₁ and Zn₂ sites of the enzymes, and two metal sites have almost equal contributions for full activity of the MβLs. The information gained in this work is helpful for the further mechanism studies and the development of the broad-spectrum MβL inhibitors.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 19","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical Tuning of Fungal Bioluminescence in Mammalian Systems","authors":"Anastasia A. Fadeeva,&nbsp;Aleksei D. Barykin,&nbsp;Andrey Bubyrev,&nbsp;Nadezhda M. Markina,&nbsp;Tatiana V. Chepurnykh,&nbsp;Anastasia A. Andrianova,&nbsp;Ekaterina S. Shakhova,&nbsp;Maxim A. Abakumov,&nbsp;Anastasiia S. Garanina,&nbsp;Renata I. Zagitova,&nbsp;Olga A. Belozerova,&nbsp;Oleg N. Yatskin,&nbsp;Andrey Yu. Gorokhovatsky,&nbsp;Cassius V. Stevani,&nbsp;Alexander S. Mishin,&nbsp;Ilia V. Yampolsky,&nbsp;Zinaida M. Kaskova","doi":"10.1002/cbic.70554","DOIUrl":"10.1002/cbic.70554","url":null,"abstract":"<p>Fungal bioluminescence is a genetically encodable platform with potential for bioimaging in mammalian systems but remains limited by low signal intensity. Here, we report a series of fungal luciferin analogs designed by modification of the arylidene fragment. Electron-donating substituents generally increase activity, whereas extension of <i>π</i>-conjugation red-shifts emission, with partial decoupling of these effects. These trends parallel those observed for firefly luciferins, indicating that empirical design principles can be transferred between the two systems. Evaluation across fungal luciferases and engineered variant v4, demonstrated broad substrate compatibility and highlighted the combined potential of luciferase engineering and luciferin modification for improving fungal bioluminescence in mammalian bioimaging.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 19","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functionalization of Peptides via Radical Arylation","authors":"Daniel R. Troeger,&nbsp;Markus R. Heinrich","doi":"10.1002/cbic.70558","DOIUrl":"https://doi.org/10.1002/cbic.70558","url":null,"abstract":"<p>Among the manifold methods for the functionalization of peptides known today, radical chemistry has so far only rarely been exploited to introduce structural modifications on this challenging type of substrate. In this short review, we give an overview showing that, especially, radical arylation reactions can represent attractive and powerful tools to access functionalized peptides under mild and biocompatible conditions where no protecting group strategy is required. Besides offering new opportunities to directly synthesize functionalized peptides for diverse biological applications, including drug development, it is also our intention to give deeper insight into aryl radical generation and aryl radical reactivity, which can, in a wider sense, be highly useful for future developments in the field of the selective radical functionalization of biomacromolecules.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 19","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.70558","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heparan Sulfate Oligosaccharides Modulate SARS-CoV-2 Spike-Host Recognition","authors":"Binjie Li,&nbsp;Tianji Zhang,&nbsp;Mingjia Yu","doi":"10.1002/cbic.70567","DOIUrl":"https://doi.org/10.1002/cbic.70567","url":null,"abstract":"<p>Heparan sulfate (HS) is a key host-factor mediator of SARS-CoV-2 attachment and an attractive target for antiviral intervention, yet the synthesis of structurally defined HS oligosaccharides remains challenging. Here, we show that a defined HS hexasaccharide, heparin-dp6, efficiently inhibits RBD-ACE2 binding and exhibits superior antiviral activity compared with longer HS mimetics. Electronic-structure analyses suggest that the strong recognition capacity of HS arises from sulfate and carboxylate groups, which create highly negative electrostatic surfaces and serve as dominant hydrogen-bond acceptors, governing charge distribution and electronic properties along the glycan backbone to modulate binding specificity and affinity. Stepwise virtual screening of a comprehensive HS database further identified several high-affinity oligosaccharides, with top candidates displaying favorable RBD-binding properties. These findings indicate that HS activity is determined not only by chain length and sulfation pattern, but also by the spatial arrangement of charged functional groups, providing mechanistic insight into HS-RBD recognition and guiding the rational design of HS-based decoy inhibitors against SARS-CoV-2 entry.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 19","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Functional Diversity Within Enzyme Families: A Practical Perspective","authors":"Nika Sokolova,&nbsp;Kristina Haslinger","doi":"10.1002/cbic.70568","DOIUrl":"https://doi.org/10.1002/cbic.70568","url":null,"abstract":"<p>Machine learning has become an increasingly powerful tool in enzyme discovery, enabling the prediction of enzyme activity, substrate scope, and functional specificity across diverse protein families. However, many reported models rely on narrowly sampled datasets and task-specific benchmarks, limiting their robustness and generalizability to distantly related enzymes or novel chemical substrates. In this concept article, we provide a practical, best-practice–oriented perspective on developing enzyme family- or class-specific machine learning (ML) predictors with an emphasis on data quality, representation, and model interpretability. We first discuss strategies for assembling biochemical datasets from literature, highlighting common sources of bias, redundancy, and uncertainty impacting downstream model performance. We then outline key considerations for generating new experimental data that are better suited for ML applications, including dataset design and coverage of enzyme and chemical space. Next, we summarize core computational steps involved in constructing enzyme and substrate representations, training and testing predictive models, and analyzing learned embedding spaces. Finally, we discuss outstanding technical challenges, such as mitigating taxonomic sampling bias, computing representations of enzymes with cofactors and post-translational modifications, and integrating predictions into design–build–test–learn cycles for real-world applications.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 19","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.70568","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward Ideal Proximity-Driven Reactions in Chemical Biology","authors":"Dominik Schauenburg","doi":"10.1002/cbic.70565","DOIUrl":"https://doi.org/10.1002/cbic.70565","url":null,"abstract":"<p>Chemical reactions in living systems are not governed solely by the intrinsic reactivity of functional groups or by the frequency of productive intermolecular collisions. Nature uses molecular recognition and spatial organization to control when and where chemical reactions occur. By selectively assembling reaction partners, biological systems increase the local concentrations, precisely orient reactive functionalities, and thereby achieve remarkable rates and selectivities under highly dilute conditions. Building on the long-established principles of molecular templation, proximity-driven reactions provide a framework for translating molecular recognition into controlled chemical reactivity in biological settings. This perspective does not seek to provide a comprehensive review of template-directed synthesis. Instead, it asks how the established principles of molecular recognition and templation are being used for the specific purposes of chemical biology, taking nucleic acid- and peptide-templated reactions, protein-based recognition platforms, proximity-driven bioconjugation, and bioorthogonal ligation strategies as case studies. I highlight how molecular templates accelerate bond formation, improve site-selectivity, and enable transformations that remain inaccessible through conventional solution-phase chemistry in the presence of competing biomolecules. Particular emphasis is placed on the quantitative coupling between three parameters that are usually discussed in isolation: the dissociation constant, which fixes the concentration window in which a template can operate; the effective molarity, which fixes the rate gain available once the complex has assembled; and the dissociation rate constant of the product complex, which fixes the ceiling on turnover frequency. Where the literature provides numbers for these quantities, they are given explicitly, and systems that achieve genuine template turnover are discussed in detail rather than treated as an aspiration. Despite substantial progress, many current systems remain limited by molecular complexity, irreversible or overly strong recognition, and the lack of efficient template regeneration. I propose that an “ideal” proximity-driven reaction should combine selective and reversible substrate recruitment, productive preorganization, rapid and chemoselective bond formation, minimal perturbation of the biological environment, and efficient template release and turnover. Future advances may therefore arise from integrating programmable molecular recognition with reversible binding and next-generation bioorthogonal ligation chemistries.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 19","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.70565","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Motif-Selective DNA Recognition and Promoter-Dependent Transcriptional Repression by a Cyclic Pyrrole/Lysine Polyamide","authors":"Mitsuharu Ooga,&nbsp;Hokun Yum,&nbsp;Yuki Hirose,&nbsp;Kaori Hashiya,&nbsp;Hiroshi Sugiyama,&nbsp;Sefan Asamitsu","doi":"10.1002/cbic.70566","DOIUrl":"https://doi.org/10.1002/cbic.70566","url":null,"abstract":"<p>Sequence-selective control of gene expression by synthetic DNA-binding molecules is attractive for developing chemical biology tools and potential therapeutic applications. Here we report a cyclic pyrrole/lysine polyamide (cPKP) that preferentially binds AT-rich DNA, with selective recognition of ATAT and ATGT motifs. In a HeLa nuclear extract-based transcription system, cPKP repressed transcription in a promoter-dependent manner, showing stronger inhibition of a cytomegalovirus (CMV) core promoter than of the human c-<i>MYC</i> promoter. RNA sequencing showed that cPKP was associated with downregulation of genes whose proximal promoters were enriched for ATAT and ATGT motifs, while causing limited perturbation of global cellular homeostasis in HeLa cells. Together, these results establish cPKP as a motif-selective DNA-binding scaffold that can modulate transcription in a promoter-dependent manner with limited global transcriptomic perturbation in human cells.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 19","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Encoding Cell-Surface Receptor Function Through Glycosylation: Lessons From CD44","authors":"María Payá-García,&nbsp;José Manuel Rojas-Marcos,&nbsp;Iris A. Bermejo,&nbsp;Diego Del Balzo,&nbsp;Ana Ardá,&nbsp;Luca Unione,&nbsp;Jesús Jiménez-Barbero,&nbsp;Ana Gimeno","doi":"10.1002/cbic.70552","DOIUrl":"https://doi.org/10.1002/cbic.70552","url":null,"abstract":"<p>Cell surface receptors are traditionally conceptualized as discrete molecular entities whose functional diversity arises primarily from gene expression and protein sequence variation. However, this view overlooks the extensive heterogeneity generated by post-translational modifications, particularly glycosylation, which can profoundly alter receptor structure, dynamics, and interactions. Increasing evidence suggests that glycosylation does not simply fine-tune receptor activity but rather defines distinct functional receptor states by modulating ligand recognition, nanoscale organization, interaction networks, and signaling competence. Among glycosylated receptors, CD44 provides a particularly informative model due to its extensive alternative splicing, dense glycosylation, and well-characterized interactions with the extracellular matrix. CD44 exhibits remarkable structural and functional plasticity and regulates diverse biological processes ranging from cell adhesion and migration to inflammation and cancer progression. Importantly, glycosylation influences CD44 interactions with its principal ligand, hyaluronan, as well as its ability to cluster, engage coreceptors, and initiate downstream signaling pathways. In this review, we discuss how glycosylation regulates CD44 function across multiple levels, from molecular recognition to membrane organization and signaling. Using CD44 as a paradigmatic example, we explore how glycosylation may shape distinct aspects of receptor function, underscoring its importance as a fundamental determinant of receptor biology and its relevance for therapeutic targeting.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 19","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.70552","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One Hundred Years of Sulfido Ligand in the Molybdenum Cofactor: New Perspectives","authors":"Silke Leimkühler,&nbsp;Benjamin R. Duffus,&nbsp;Carola Schulzke","doi":"10.1002/cbic.70527","DOIUrl":"https://doi.org/10.1002/cbic.70527","url":null,"abstract":"<p>The xanthine oxidase (XO) family of mononuclear molybdoenzymes consists of well-studied enzymes like XO, xanthine dehydrogenase (XDH), and aldehyde oxidase (AO) in eukaryotes. The characteristic of this family is a terminal sulfido ligand bound to the active site Mo or W ion. Historically, these enzymes were among the first to be investigated in a purified form. Since its discovery in 1902 in cow's milk, the XO enzyme is among the best-studied molybdoenzymes. Much pioneering work has been carried out including comprehensive spectroscopic and structural analyses to study the enzymes’ molybdenum center. This led to the discovery that the enzyme produces superoxide and thereby inactivates itself by removal of the essential sulfido ligand at the active site. This sulfido ligand has been later discovered also in enzymes of the dimethyl sulfoxide (DMSO) reductase family. In this review, we describe historical aspects on the discovery and role of the sulfido ligand in the two enzyme families, contextualize new discoveries, and provide perspectives for future investigations into still elusive research questions urgently requiring determination, which may or may not span yet another 125  years.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"27 19","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.70527","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149146421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}